Cheng

Review
pubs.acs.org/CR
Functional Nanomaterials for Phototherapies of Cancer

Liang Cheng, Chao Wang, Liangzhu Feng, Kai Yang, and Zhuang Liu*
Institute of Functional Nano & Soft Materials (FUNSOM) & Collaborative Innovation Center of Suzhou Nano Science and
Technology, Soochow University, Suzhou 215123, China
2.5.1. Light-Controllable Drug Release Based
on the Photothermal Eect of Nano-
carriers 10903
2.5.2. Photothermally Enhanced Drug Deliv-
ery 10904
2.5.3. Gold Nanomaterials for PTT-Based Can-
cer Combination Therapy 10904
2.5.4. Other Inorganic Nanomaterials for PTT-
Based Cancer Combination Therapy 10907
2.5.5. Organic NIR-Absorbing Nanoagents for
CONTENTS PTT-Based Cancer Combination Therapy 10909
1. Introduction 10869 3. Photodynamic Therapy Based on Nanomaterials 10910
2. Photothermal Therapy Using Nanoagents 10872 3.1. Organic Nanoparticles as Nanocarriers of
2.1. Gold Nanostructures for Photothermal Ther- Photosensitizers for Photodynamic Therapy 10910
apy 10872 3.2. Inorganic Nanoparticles as Nanocarriers of
2.1.1. The Plasmonic Absorbance of Gold Photosensitizers for Photodynamic Therapy 10913
Nanostructures 10872 3.2.1. Silica Nanoparticles 10913
2.1.2. Gold Nanoparticles 10874 3.2.2. Metallic Nanoparticles 10916
2.1.3. Gold Nanorods 10876 3.2.3. Magnetic Nanoparticles 10917
2.1.4. Gold Nanoshells 10878 3.2.4. Semiconducting QDs 10919
2.1.5. Gold Nanocages, Nanostars, and Other 3.2.5. Fullerenes and Their Derivatives 10920
Nanostructures 10879 3.2.6. Other Nanocarbons 10921
2.1.6. Gold-Shelled Nanocomposites for Imag- 3.2.7. Two-Photon Exciting Nanoparticles 10924
ing-Guided Therapy 10881 3.2.8. Scintillation Nanoparticles and Self-
2.1.7. Toxicology Studies of Gold Nanomateri- Illuminating Nanoparticles 10925
als 10883 3.2.9. Upconversion Nanoparticles for Near-
2.2. Carbon Nanomaterials for Photothermal Infrared-Induced Photodynamic Ther-
Therapy 10885 apy 10925
2.2.1. Carbon Nanotubes 10885 3.3. Combination of Photodynamic Therapy with
2.2.2. Nanographene 10887 Other Therapeutic Approaches 10928
2.2.3. Carbon-Based Composite Nanostruc- 3.3.1. Combination of Photodynamic Therapy
tures 10888 with Chemotherapy 10929
2.2.4. Toxicology Studies of Carbon Nanoma- 3.3.2. Combination of Photodynamic Therapy
terials 10890 with Photothermal Therapy 10929
2.3. Other Inorganic Nanomaterials for Photo- 4. Future Challenges and Prospects 10930
thermal Therapy 10890 Author Information 10931
2.3.1. Pd Nanosheets 10890 Corresponding Author 10931
2.3.2. CuS Nanostructures 10891 Notes 10931
2.3.3. Other Inorganic Photothermal Nano- Biographies 10931
agents 10894 Acknowledgments 10932
2.4. Organic Nanoparticles for Photothermal References 10932
Therapy 10896
2.4.1. NIR-Absorbing Dye Containing Nano-
1. INTRODUCTION
complexes 10896
2.4.2. NIR-Absorbing Conjugated Polymers 10899 Cancer has been one of the major threats to the lives of human
2.4.3. Porphysomes 10901 beings for centuries.1 Current cancer therapies mainly include
2.4.4. Other NIR-Absorbing Organic Nano- surgery, chemotherapies, and radiotherapies. While surgery in
particles 10902 many occasions is not able to completely remove all cancer cells
2.5. Combination of Photothermal Therapy with
Other Therapeutic Approaches 10903 Received: September 25, 2013
Published: September 26, 2014
2014 American Chemical Society 10869 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939
Chemical Reviews Review
Figure 1. Statistics of publications and their citations with topics including photo, nano, and therapy, based on Web of Science searching
conducted on August 15th, 2014.
in the human body, chemotherapy and radiotherapy all suer reported ones,9,10 as well as organic nanoparticles such as NIR-
from their severe toxic side eects to normal tissues and limited absorbing conjugated polymers,11,12 porphysomes,13 and nano-
specicities to cancer cells.2 Phototherapies induced by light, micelles encapsulated NIR dyes,14 have been widely explored
preferably near-infrared (NIR) light with superior tissue by many research groups including ours as photothermal agents
penetration ability, usually involve phototherapeutic agents for PTT ablation of cancer cells in vitro and in vivo. In addition,
with little toxicity in dark, and are able to selectively kill cancer the photothermal eect of nanoagents can not only be used to
cells under light irradiation, without causing much damage to directly burn cancer cells, but is also helpful to trigger and/or
normal tissues in dark. There are two levels of selectivity in enhance other therapeutic approaches if well-designed smart
photo therapy: (1) The well-engineered phototherapeutic nanoplatforms are employed, aiming at the synergistic cancer
agents (e.g., nanoagents) could selectively target tumor via killing eect.
either passive or active tumor homing. (2) The light Dierent from PTT, which relies on photothermal heating to
illumination could be spatially controlled to irradiate only the cook cancer, photodynamic therapy (PDT) uses singlet
diseased lesion (e.g., the tumor) without damaging normal oxygen (SO) or reactive oxygen species (ROS) generated from
tissues. Such dual-selectivity oered by phototherapies could photosensitizer (PS) molecules under light exposure to kill
signicantly reduce the systemic toxicity associated with cancer cells.15 PDT is an externally activable treatment
traditional chemo- or radio-therapeutic approaches. With the modality for various diseases, and has already been approved
rapid development of nanoscience and technology in the past for cancer treatment in the clinic. Upon administration of PS
decade, phototherapies based on nanomaterials and nano- molecules, the lesion is then selectively illuminated with light of
technologies have attracted tremendously increasing interest appropriate wavelength, which, in the presence of oxygen, leads
(Figure 1). to the generation of cytotoxic oxygen species by PS molecules
Photothermal therapy (PTT) employs photoabsorbing and consequently to cell death and tissue destruction. A wide
agents to generate heat from light, leading to thermal ablation range of PS molecules, most of which contain porphyrin
of cancer cells and the subsequent cell death. Ideal photo- structures, have been applied in the PDT. Over the past decade,
thermal agents should exhibit strong absorbance in the NIR nanoparticle-based PDT has emerged as an alternative to
region, which is a transparency window for biological tissues, conventional PDT to eectively target cancer. PS-carrying
and could eciently transfer the absorbed NIR optical energy nanoparticles could increase the water solubility of PS
into heat. In addition, the agents used in PTT should be molecules, enhance their tumor accumulation, and thus
nontoxic and show high tumor-homing ability, to improve improve the therapeutic ecacy and specicity of PDT. In
therapeutic ecacy without rendering toxic side eects. Various addition, nanotechnology provides a platform for the
nanomaterials with strong NIR absorbance have shown great integration of multiple functionalities in a single construct.
promise in photothermal treatment of cancer, achieving Various nanomaterials such as liposomes,16 polymeric nano-
encouraging therapeutic ecacies in many in vivo animal particles,17 magnetic nanoparticles,1820 quantum dots,21
studies. Inorganic nanomaterials including dierent gold carbon-based nanomaterials,22 mesoporous silica nanopar-
nanostructures,3,4 carbon nanomaterials,5 palladium nano- ticles,23 as well as a number of other functional nanoparticles
sheets,6 copper sulde nanoparticles,7,8 and a few other newly with interesting chemical and physical properties24 have been
10870 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939
Table 1. A Summary of Functional Nanomaterials Developed for Photothermal and Photodynamic Therapy
types of
nanoagents references remarks
photothermal Au nanoparticles 3957 gold nanostructures have been extensively explored as photothermal agents; their absorbance spectra
therapy Au nanorods 28,5866 could be easily tuned by controlling their sizes and morphology; gold is a rather inert element with
reasonable biocompatibility
Au nanoshells 68,7082
Au nanocages 8385
Au nanostars 37,86,87
Au nanoprisms 88,89
AuAg alloyed 90,91
metallic
Au-based 9297,102,106108
nanocomposites
carbon nanotubes 131144 carbon nanomaterials usually show broad absorbance from UV to NIR with excellent photothermal
nanographene 157,164167,170 stability; the toxicity of nanocarbons is closely related to their surface chemistry
carbon 171 179
nanocomposites
Pd nanosheets 6,196198 those inorganic photothermal agents containing heavy metal elements are recently developed ones;
CuS 7,8, 199202,204,205 many of them could be utilized for imaging-guided PTT; their potential long-term toxicity remains to
nanostructures be explored
transition-metal 9,10
dichalcogenides
wungsten oxide 214
nanowires
indocyanine green 216,218,225 ICG is a clinically approved agent; small molecules usually could be rapidly excreted by renal excretion
heptamethine 14
indocyanine dye
polyaniline 236 conjugated polymers have been found to be robust photothermal agents; their biodegradation
nanoparticles behaviors remain to be studied
polypyrrole 11,237,242
nanoparticles
PEDOT:PSS 12
nanoparticles
PCPDTBT, 238
PCPDTBSe
porphyrin-lipid 13,243,244 those organic agents may have great biocompatibility
nanodevices
melanin 246
nanoparticles
photodynamic silica 363373 many inorganic nanoparticles could be loaded with photosensitizers for photodynamic therapy; some
therapy nanoparticles of them (e.g., fullerene derivatives) are intrinsic PS agents; the future clinical use of those inorganic
metallic 376382 nanoagents is again limited by their long-term in vivo retention and toxicity concerns
nanoparticles
magnetic 383387
nanoparticles
semiconducting 21,393396
QDs
fullerenes and 400405
their derivatives
carbon nanotubes 22,406409
nanographene 23,410413
carbon dots 414,415
scintillation 420422 able to deliver PDT without the need of external light sources
nanoparticles
upconversion 25,26,430,433,436438,441 able to trigger PDT under NIR light via resonance energy transfer
nanoparticles
liposomes 345 organic nanocarriers for PDT have been studied for decades; some of them are already in clinical trials
micelles 351355
natural degradable 356359
polymers
dendrimers 360
hollow polymer 17,361,362
microcapsules
developed for the delivery of PDT, showing encouraging results This article would comprehensively review the recent
in vitro and in vivo. Moreover, in recent years, another unique advances regarding the development of phototherapies for
class of optical nanomaterials, upconversion nanoparticles cancer treatment, such as PTT, PDT, and phototriggered
(UCNPs), which emit high-energy visible light under NIR combined therapy, using functional nanomaterials (Table 1). A
excitation, have been developed to realize NIR-induced PDT large variety of inorganic and organic NIR-absorbing nanoma-
for improved tissue penetration.25,26 terials explored for PTT cancer treatment will be summarized.
Figure 2. Plasmonic absorbance and transmission electron microscopy (TEM) images of various types of Au nanostructures. (a and e) Au
nanoparticles (AuNPs). Reprinted with permission from ref 33. Copyright 2013 Elsevier. (b and f) Au nanorods (AuNRs). Reprinted with
permission from ref 32. Copyright 2010 Elsevier. (c and g) Au nanocages (AuNCs). Reprinted with permission from ref 34. Copyright 2008
American Chemical Society. (d and h) Au nanostars or nanoowers (AuNFs). Reprinted with permission from ref 37. Copyright 2012 Institute of
Physics.
The combination of PTT with other therapeutic approaches research groups.4,2732 Most of these applications are based on
such as chemotherapy and gene therapy will then be discussed. an optical phenomenon known as localized surface plasma
Various dierent types of nanoagents developed for the delivery resonance (LSPR). The optical properties of gold nanostruc-
of PDT, as well as combined PDT with other therapies, will tures are determined by the size and the shape of the
also be reviewed. The future prospects and challenges in this nanoparticle. Figure 2 shows the structures and the typical
rapidly growing eld will be addressed at last. absorbance spectra of several types of representative gold
nanostructures, icnluding gold nanoparticles (AuNPs), gold
2. PHOTOTHERMAL THERAPY USING NANOAGENTS nanorods (AuNRs), gold nanocages (AuNCs), and Au
nanostars or Au nanoowers (AuNFs). Spherical AuNPs
2.1. Gold Nanostructures for Photothermal Therapy usually show the LSPR peak at 520 nm, with the slightly
2.1.1. The Plasmonic Absorbance of Gold Nanostruc- red-shifted absorbance as the increase of nanoparticle
tures. Gold nanostructures provide a versatile, multifaceted diameter.33 By changing the morphology of gold nanostruc-
platform for a broad range of biomedical applications for both tures, their LSPR peak can be tuned to the NIR region. The
cancer diagnosis and therapies as demonstrated by numerous optical absorption of AuNSs can be tuned to the NIR range by
Figure 3. Development of amphiphilic plasmonic micelle-like nanoparticles (APMNs) based on self-assembled AuNPs coated with block
copolymers. Depending on the lengths of polymer tethers and the sizes of AuNP cores, dierent structures including unimolecular micelles, clusters,
as well as vesicles could be formed by self-assembly. APMNs with red-shifted absorption were then used for in vivo photothermal ablation of tumors
in mice. Reprinted with permission from ref 53. Copyright 2013 American Chemical Society.
Figure 4. PEGylated AuNRs for in vivo tumor photothermal therapy. (a) A TEM image of NIR-absorbing AuNRs. (b) A schematic showing surface
PEGylation on AuNRs. (c) A photo of a mouse bearing two MDA-MB-435 tumors on its opposing anks. PEG-AuNRs or saline were iv given (20
mg/kg) to tumor-bearing mice bearing. After AuNRs had cleared from circulation (72 h after injection), the right ank was irradiated using an 810
nm diode laser (2 W/cm2; beam size indicated by dotted circle). (d) Infrared (IR) thermal images of photothermal heating for PEG-AuNR-injected
(top) and saline-injected (bottom) mice under laser irradiation. (e) Photos showing AuNR-based photothermal destruction of tumors in mice.
Reprinted with permission from ref 64. Copyright 2009 American Association for Cancer Research.
varying the relative size of the core and shell. AuNRs typically 520 nm and the other for the longitudinal mode whose position
have two LSPR peaks,32 one for the transverse mode around strongly depends on the aspect ratio of the nanorod and can be
Figure 5. Targeted hollow gold nanoshells (HAuNS) for photothermal ablation therapy. (a) A scheme for c(KRGDf)-PEG-HAuNS bioconjugation.
(b) Characterization of HAuNS by TEM (bar, 20 nm) and UVvisNIR spectrum. (c) Representative bioluminescence images of nude mice
bearing U87-TGL tumors with dierent treatments. (d) Quantitative analysis of bioluminescence images beginning with treatment administration on
day 8 after tumor inoculation (n = 5 per group). (e) KaplanMeier survival curve of tumor-bearing mice after various treatments indicated in (c) (n
= 10 per group). Reprinted with permission from ref 81. Copyright 2009 American Association for Cancer Research.
nely tuned from visible to NIR region.28 AuNCs invented in using the laser-induced bubble formation mechanism under
2002 by the Xia group are hollow cubic Au nanostructures with nanosecond laser pulses with AuNPs as the photothermal
ultrathin porous walls and truncated corners.34,35 The LSPR agent.4143 On the basis of the approach, in vivo tumor ablation
peaks of AuNCs can be tuned to any wavelength in the range of in rats with AuNPs was also realized in a recent study using
6001200 nm by controlling the size or wall thickness of the pulsed laser irradiation.44 Intracellular bubble formation from
AuNCs. AuNFs, or named Au nanostars, which contain AuNPs could result in individual tumor cell damage. However,
multiple sharp branches with plasmonic absorbance tunable rather expansive pulsed lasers are required in this technique and
in the NIR region, have also gained wide interest in recent usually used to irradiate small localized regions. Moreover, the
years.36 The extinction spectra of individual AuNFs vary greatly overall heating eciency is relatively low due to rapid heat loss
due to the unavoidable shape polydispersity, whereas that of a after the short irradiation pulses.
AuNFs solution typically exhibits broad visible and NIR The use of continuous wave (CW) laser during PTT has its
absorbance due to the overlapping of many distinctive advantage in terms of eective heat accumulation to induce
spectra.37,38 tumor ablation in a larger area. In the study by EI-Sayed et al.,
2.1.2. Gold Nanoparticles. With a much higher absorption AuNPs were conjugated to an anti-EGFR antibody to target
cross-section than small organic dyes, AuNPs usually exhibit two types of human head and neck cancer cells.45 It was found
strong visible absorption, whose peak could be aected by the that the photothermal heating of AuNPs could induce cancer
diameter and aggregation state of AuNPs. Photothermal cell death after the irradiation with a CW laser with a
ablation of cancer can be achieved using AuNPs under wavelength of 514 nm for 4 min at the power density of at 19
irradiation by visible lasers. In 2003, Lin and co-workers used W/cm2, while healthy cells showed little loss of cell viability
pulsed laser to heat cancer cells treated with AuNPs, and under the same treatment. A number of other groups have also
realized highly localized photothermolysis of targeted lumpho- reported the use of AuNPs as a photothermal agent for eective
cytes cells.39 At about the same time, Zharov et al. reported a cancer cell ablation under irradiation by CW visible lasers.4649
similar study on the photothermal destruction of K562 cancer Although AuNPs can be readily synthesized and have been
cells by AuNPs.40 In this work, they detected the laser-induced extensively explored in the area of nanomedicine, the major
bubbles during the laser irradiation of AuNPs, and investigated limitation of using AuNPs in photothermal cancer treatment is
their formation dynamics during the pulsed laser treatment. their relatively short absorption wavelength in the visible region
Later, they carried out further studies and demonstrated this (520 nm). Because visible light would be strongly absorbed
technique in the treatment of dierent types of cancer cells and scattered by biological tissues, the penetration depth of
Figure 6. Gold nanocages for in vitro and in vivo photothermal therapy. (a) Normalized UVvisNIR extinction spectra recorded from aqueous
suspensions of nanostructures after titrating Ag nanocubes with dierent amounts of a HAuCl4 aqueous solution. (b) A scanning electron
microscopy (SEM) image of AuNCs prepared by reuxing an aqueous solution containing both Ag nanocubes and HAuCl4. The inset shows a TEM
image of the as-made AuNCs. (c) SK-BR-3 breast cancer cells were treated with immuno AuNCs and then irradiated by an 810 nm laser at a power
density of 1.5 W/cm2 for 5 min. (c1) Calcein AM assay, and (c2) ethidium homodimer-1 (EthD-1) assay. In the control experiment, cells irradiated
under the same conditions but without immuno AuNCs treatment maintained viability, as indicated by (c3) calcein uorescence assay and (c4) the
lack of intracellular EthD-1 uptake. Cells treated with immunoAuNCs but irradiated at a lower power density (0.5 W/cm2) for 5 min remained alive,
as shown by (c5) calcein uorescence assay and (c6) the lack of intracellular EthD-1 uptake. (d) Photograph of a tumor-bearing mouse under the
photothermal treatment. (d1d8) IR thermal images of (d1d4) nanocage-injected and (d5d8) saline-injected tumor-bearing mice at dierent
time points: (d1, d5) 1 min, (d2, d6) 3 min, (d3, d7) 5 min, and (d4, d8) 10 min. Reprinted with permission from ref 83. Copyright 2007 American
Chemical Society. Reprinted with permission from ref 85. Copyright 2010 John Wiley & Sons, Inc.
AuNP-based PPT is usually rather limited. To overcome this PEGylated AuNPs. A preliminary photothermal tumor ablation
problem, there have been a number of recent reports taking evaluation suggested that the aggregation of AuNPs could be
advantage of the aggregation-induced red-shift of AuNP applied in cancer NIR PTT.
absorption for photothermal cancer ablation,5057 Kim and Well-designed self-assemblies of AuNPs with red-shifted
co-workers designed and synthesized smart AuNPs that could absorption have also been explored for applications in
be responsible for pH changes and form aggregates in acidic photothermal therapy. In recent years, Nie and co-workers
pH.50 When exposed to an acidic environment after cell reported self-assemblies of amphiphilic plasmonic micelle-like
internalization, those smart AuNPs began to aggregate, AuNPs with the help of linear block copolymers (BCPs)53
showing greatly red-shifted absorbance to NIR, useful for (Figure 3). In a mixture of water/tetrahydrofuran, Au micelle-
photothermal ablation of cancer cells under NIR light exposure. like nanoparticles would be assembled into various super-
Recently, the same group further investigated pH-responsive structures. The assemblies of Au micelle-like nanoparticles
assembly of AuNPs and spatiotemporally concerted drug resulted in strong absorption in NIR range due to the
release for synergistic cancer therapy.51 In another work, Liu remarkable plasmonic coupling of Au cores, thus facilitating
et al. used a simple method to prepare AuNPs by surface their biomedical applications in bioimaging and photothermal
modication with mixed-charge zwitterionic self-assembled cancer therapy.5356 Another work by Liu et al. also developed
monolayers, which could be stable at the pH of blood and a simple strategy for simultaneous assembly of small-size
normal tissues but aggregate instantly in response to the acidic AuNPs to form a novel nanocomposite in the presence of gum
extracellular pH of solid tumors.52 The total accumulation, arabic as an ecient photothermal agent for killing cancer
retention, and cell uptake of the pH-responsive AuNPs in cells.57 Therefore, although the plasmonic absorbance of
tumors were signicantly enhanced by the pH-induced individual AuNPs themselves usually locates in the visible
aggregation eect as compared to that of nonsensitive range, their self-assembled nanostructures with red-shifted
Figure 7. Schematic representation of the synthesis of monoclonal anti-PSMA antibody- and A9 RNA aptamer-conjugated popcorn-shaped AuNFs
for in situ monitoring of photothermal therapy response using surface-enhanced Raman scattering (SERS). The disappearance of SERS signals
indicated the accomplishment of photothermal cancer cell ablation in this study. Reprinted with permission from ref 86. Copyright 2010 American
Chemical Society.
absorbance to the NIR window are promising for in vivo eects of folate-conjugated AuNRs to human malignant
photothermal cancer treatment with improved tissue pene- nasopharyngeal carcinoma (KB) cells by both continuous-
tration. wave NIR laser and femtosecond-pulsed laser irradiation.58
2.1.3. Gold Nanorods. Among various Au nanostructures, They found that the photothermolysis of KB cells with a high
AuNRs that can be easily synthesized by seeded growth expression of folate receptors (FR) was much more eective
methods have been extensively explored in PTT due to their than that of normal NIH/3T3 cells with a lower level of FR
strong optical extinction in the visible and NIR region.3 By expression. Several other groups have also reported that AuNRs
simply increasing the aspect ratio of nanorods, the strong could be used as promising agents for in vitro cancer cell
longitudinal plasma absorption band of AuNRs can be tuned to photothermolysis.5963
the longer wavelength. There have been numerous examples of In the case of in vivo PTT, Van Maltzahn et al. reported that
methods to conjugate AuNRs with biomolecules for cell polyethylene glycol (PEG) coated AuNRs (AuNR-PEG) could
targeting or intracellular delivery. As early as 2006, El-sayed et be used as an ecient photothermal nanoheater.64 In their
al. demonstrated that AuNRs could be used for in vitro work, AuNR-PEG exhibited a long blood half-life of 17 h after
molecular imaging and PTT.28 Antibody-conjugated AuNRs intravenous (iv) injection into tumor-bearing mice (20 mg Au/
showed a high binding anity to the cell membrane of kg) and could accumulate in tumor at 7% ID/g at 72 h post
malignant cells over that of normal cells, allowing selective injection. It was found that the tumors on mice iv injected with
destruction of tumor cells without harming healthy cells after AuNR-PEG were rapidly heated to over 70 C by laser
laser irradiation. Tong et al. also investigated the photothermal irradiation (810 nm, 2 W/cm2, 5 min), whereas the control
Figure 8. Au nanoprisms for photothermal therapy. (a) A scheme of the synthetic method to produce PEGylated Au nanoprisms functionalized with
glucose (Glc) and the dye TAMRA. (b) UVvisNIR spectra of puried solutions (nanoprisms@PEG) corresponding to the preparations with
dierent volumes of the reductant added. (cf) SEM images of Au nanoprisms with increasing average edge length. The scale bars are 500 nm in all
cases. (g,h) Calcein AM (green staining, live cells) and EthD-1 (red staining, dead cells) costained cells after incubation with Au nanoprisms and
laser irradiation. The laser spot was focused at the center in (h). Reprinted with permission from ref 88. Copyright 2012 American Chemical Society.
Figure 9. Magnetic gold nanocomposites. (ae) Multifunctional magnetic AuNSs for magnetic resonance imaging and photothermal therapy. (a)
Synthesis of the magnetic AuNSs (Mag-GNS). (be) TEM images of (b) amino-modied silica spheres, (c) silica spheres with Fe3O4 (magnetite)
nanoparticles immobilized on their surfaces, (d) silica spheres with Fe3O4 and gold nanoparticles immobilized on their surfaces, and (e) the Mag-
GNS. (fj) Monodisperse superparamagnetic Fe3O4 core@hybrid@Au shell nanocomposite for bimodal imaging and photothermal therapy. (f) A
schematic diagram for the fabrication of Fe3O4@hybrid@Au nanocomposite. (gj) SEM images of Au-SSCNs (g and h) and Fe3O4 @hybrid@Au
nanocomposites (i and j). Reprinted with permission from refs 92 and 94. Copyright 2006 and 2011 John Wiley & Sons, Inc.

uptake of RGD-dAuNRs over time. They further observed the

disappearance of tumors after iv injection of RGD-dAuNRs and
NIR laser irradiation (808 nm, 24 W/cm2, 5 min). In another
study, Choi et al. synthesized AuNRs loaded into chitosan-
conjugated pluronic-based nanocarriers that could selectively
target the tumor.59 Those AuNRs showed a rather high tumor
uptake at over 20% of injected dose per gram tissue (%ID/g),
in marked contrast to PEG modied AuNRs, which exhibited
the tumor uptake at only 7%ID/g. After iv injection of the
AuNRs-loaded, chitosan-conjugated nanocarriers, and the
followed NIR laser irradiation of the tumor, rather ecient in
vivo thermolysis of tumors was achieved, without showing any
apparent damage to the surrounding healthy tissues.
Figure 10. Magnetic targeting enhanced photothermal cancer 2.1.4. Gold Nanoshells. Gold nanoshells (AuNSs) are
treatment under the guidance of multimodal imaging using PEGylated, usually core/shell particles comprising a gold shell formed on
gold-coated iron oxide nanoclusters. Reprinted with permission from top of a dielectric silica core, and can be easily synthesized by
ref 98. Copyright 2014 John Wiley & Sons, Inc. the seed-mediated shell growth.27,67,68 AuNSs are attractive in
PTT because their LSPR can be easily tuned to the NIR region
mice showed the maximum surface temperature at 40 C simply by modifying the thickness of the shell.6870 In 2005,
(Figure 4). Thus, tumors on mice that received AuNR-PEG Halas and co-workers demonstrated that AuNSs conjugated
through iv injection completely disappeared within 10 days with anti-HER2 antibody could be used for dark-eld imaging
after NIR laser irradiation, in marked contrast to the control and PTT of SKBR3 breast carcinoma cells.70 In 2007, the same
groups, which showed uninhibited tumor growth. Moreover, group also investigated the use of AuNSs for in vivo
the survival time of mice who received AuNR-PEG injection enhancement of optical coherence tomography (OCT) imaging
and the followed PTT treatment was over 50 days as compared as well as eective photothermal ablation of tumors.68 In this
to 33 days for control groups. Similar results using PEGylated work, thiolated PEG (PEG-SH) conjugated AuNSs were iv
AuNRs for in vivo PTT cancer treatment have also been injected into tumor-bearing mice for OCT imaging, following
reported by Dickerson et al. in another work.65 which the tumors were irradiated using a NIR laser (808 nm, 4
Beside simply relying on the ERP eect for tumor passive W/cm2, 3 min) for photothermal ablation.
tumor, active tumor targeting with AuNR bioconjugates for Besides the use of silica nanoparticles as the cores to fabricate
eective in vivo PTT has also been achieved by a number of AuNSs, many other methods have been developed to
groups. Li et al. demonstrated in vivo tumor targeting and PTT synthesize AuNSs based on dierent core materials. Liu and
using dendrimer-modied AuNRs (dAuNRs) conjugated with co-workers reported a new approach toward the design of
arginine-glycine-aspartic acid (RGD) peptide, which binds AuNSs on carboxylated polystyrene spheres (AuNRCPSs).71
integrin v3 overexpressed on tumor vasculatures and several The higher refractive index of polystyrene, as compared to
types of tumor cells.66 The biodistribution data of RGD- silica, resulted in a somewhat narrower NIR plasma resonance
dAuNRs revealed 47% of the injected RGD-dAuNRs in the absorbance peak of AuNRCPSs, enhancing their NIR-absorbing
blood at 3 h p.i., 17% of the injected RGD-dAuNRs in the as well as photothermal eciency. Ke et al. developed a novel
tumor at 6 h post injection, and the gradually increased tumor multifunctional theranostic agent based on Au nanoshelled
Figure 11. Multifunctional nanoparticles (MFNPs) based on upconversion nanoparticles as the cores for imaging-guided cancer therapy. A
schematic illustration showing the composition of a PEGylated MFNPs (MFNP-PEG) and the concept of in vivo imaging-guided magnetically
targeted PTT. After iv injection of MFNP-PEG, a magnet was attached to the tumor to enhance the nanoparticle tumor accumulation, which was
revealed by bimodal MR and upconversion imaging. In vivo PTT was further carried out to enable eective tumor ablation. Reprinted with
permission from ref 107. Copyright 2012 Elsevier.

Figure 12. Single-walled carbon nanotubes (SWNTs) for in vivo NIR mediated photothermal tumor destruction. (a) Scheme of PEGylated SWNTs
(PEG-SWNTs). Inset: A photo showing PEG-SWNTs stably dispersed in fetal bovine serum and phosphate buer saline (PBS). (b) Atomic force
microscope (AFM) image of individual PEG-SWNTs deposited on a SiO2 substrate. The scale bar is 500 nm. (c) A scheme showing in vivo
photothermal treatment using PEG-SWNTs. (d) Photographs of a mouse bearing a xenograft KB tumor (70 mm3) after i.t. injection of PEG-
SWNTs (120 mg/L, 100 L) and then exposure to the NIR laser irradiation (808 nm, 76 W/cm3) for 3 min to induce the tumor ablation. Reprinted
with permission from ref 139. Copyright 2009 American Chemical Society.
microcapsules (AuNS-MCs) by the electrostatic adsorption of Treatment Centers of America (CTCA) and Nanospetra
AuNPs as seeds on the polymeric microcapsule surfaces, Biosciences have carried out the rst clinical trial for the
followed by the formation of AuNSs by using the seed- treatment of lung cancers by phtotothermal therapy that uses
mediated growth.72 Those AuNS-MCs could be utilized for AuNSs invented by Halass group at Rice University. The
both PTT cancer ablation and photoacoustic (PA) imaging of therapy begins with an injection of AuNSs into the patients
cancer. Recently, lipid vesicles (such as liposomes) have also bloodstream. After 1224 h to allow enough time for the
been used as the templates to prepare hollow AuNSs as tumor accumulation of AuNSs, a NIR laser is used to heat
photothermal agents.7375 AuNSs and destroy tumors in the patient. This clinical trial is in
Because of their ease of functionalization, AuNSs are often its phase II stage right now, to our best knowledge.82
conjugated with targeting ligands for targeted PTT both in vitro 2.1.5. Gold Nanocages, Nanostars, and Other Nano-
and in vivo.7679 In 2009, Lu et al. investigated in vivo tumor structures. Gold nanocages (AuNCs) represent another novel
targeting by PEGylated AuNSs conjugated with a melanocyte- class of nanostructures rst developed by Xia and co-workers in
stimulating hormone (MSH) analogue for selective photo- 2002.34 AuNCs could be prepared by galvanic replacement
thermal ablation of melanoma tumors.80 In 2011, Lu et al. between Ag nanocubes and HAuCl4 in an aqueous solution. In
further showed that iv injection of RGD peptide conjugated 2007, Xias group demonstrated the selective photothermal
AuNSs could target glioma tumors with high integrin v3 destruction of SK-BR-3 breast cancer cells in vitro using
expression, enabling photoacoustic tomography (PAT) and immuno-AuNCs functionalized with the anti-HER-2 antibody
selective PTT of an orthotopic mouse xenograft model of (Figure 6ac).83,84 After incubation with the immuno-AuNCs,
glioma (Figure 5).81 It was also found that the photothermal SK-BR-3 breast cancer cells were irradiated with a femtosecond
treatment signicantly prolonged the survival of tumor-bearing laser at varying power densities for 5 min. When the AuNCs
mice. were incorporated, a well-dened area of cellular death
AuNSs have not only been demonstrated to be an eective corresponding to the laser spot was observed. Later in 2010,
class of photothermal agents in preclinical animal experiments, they switched to an in vivo tumor mouse model to examine the
but, more excitingly, also entered clinic trails. Recently, Cancer ecacy of AuNCs for photothermal cancer treatment in
Figure 13. In vivo tumor photothermal therapy using iv injected SWNTs with the optimized surface coating. (a) A scheme of a SWNT with PEG-
PMHC18 polymer coating. Right table: A list of 10 PEG-PMHC18 polymers synthesized in this work. Nine of them were successfully used to
solubilize SWNTs. The 10%-5k version was found to be the optimized coating molecule that oered SWNTs long blood circulation time, ecient
tumor uptake, and relatively low retention in other organs such as liver, spleen, and skin. SWNTs functionalized by 10%-5k PEG-PMHC18 polymer
were thus used for the followed photothermal therapy. (b) Representative photos of tumors on mice after various treatments indicated. (c) The
tumor growth curves of dierent groups after treatment. Reprinted with permission from ref 142. Copyright 2011 Elsevier.
mice85(Figure 6d). After iv injection of PEG-AuNCs for 3 days, potential of AuNFs as an ecient photothermal agent in cancer
the tumor on each mouse was irradiated with an 808 nm therapy.87
continuous-wave laser at a power density of 0.7 W/cm2 for 10 There are some other types of Au nanostructures with NIR
min, during which the tumors containing AuNCs were rapidly absorption useful for PTT. Au nanoprisms (AuNMs) are
heated to over 55 C, leading to eective ablation of those triangular shaped Au discs that have tunable optical properties
tumors. in the NIR.88 Pelaz et al. described a novel and straightforward
Another type of NIR-absorbing Au nanostructures utilized wet-chemical synthetic route to produce biocompatible single-
for PTT is Au nanostars, or Au nanoowers (AuNFs), which crystalline AuNMs,88 which could eectively ablate Vero cells
were spherical nanoparticles with multiple sharp edges and a after 2 min of 1064 nm NIR illumination at 30 W/cm2, that
high absorption-to-scattering ration in the NIR region, however was a rather high power density (Figure 8). Wang et
favorable for photothermal heat generation.37,86 Lu et al. al. synthesized AuNMs and compared them with AuNRs and
AuNCs.89 They found that AuNMs exhibited a comparable
reported a multifunctional AuNFs-based surface-enhanced
photothermal eciency, higher cell uptake, and lower
Raman scattering (SERS) assay for targeting sensing, PTT
cytotoxicity relative to AuNRs and AuNCs.
treatment, and in situ monitoring of the PTT response during
Coreshell and alloyed multimetallic Au-based nanomateri-
the therapy process36,86 (Figure 7). When AuNFs were als are also interesting nanomaterials in PTT. Particularly, Au
attached to cancerous cells, the localized heating that occurred Ag nanocomposites possess sharper and stronger longitudinal
during NIR irradiation was able to cause irreparable cellular LSPR bands than the corresponding Ag or Au nanostructures.
damage. In another work, Yuan et al. showed that TAT-peptide Hu et al. synthesized a new class of AuxAg1x nanostructures
functionalized AuNFs entered cells signicantly more than bare with dendrite morphology by using a replacement reaction
or PEGylated AuNFs.36 After 4 h incubation of TAT-AuNFs between Ag dendrites and an aqueous solution of HAuCl4.90
with BT549 breast cancer cells, ecient photothermolysis was The hollow Au0.3Ag0.7 dendrites with strong NIR absorption
accomplished using a NIR laser under 0.2 W/cm2, which was showed good biocompatibility and could serve as an eective
among the lowest power densities ever reported for pulsed photothermal agent. In a recent work, Tan and co-workers
lasers. The photothermal ablation in vivo was demonstrated designed an aptamer-based nanostructure, which combined the
using PEGylated AuNFs on mice. Their results illustrated the high absorption eciency of AgAu nanorods with the target
Figure 14. Chirality enriched SWNTs for photothermal therapy at the ultralow dose. (a) Photoluminescence emission (PLE) spectrum of SWNTs
after chirality separation. Inset is the PLE spectrum of SWNTs before separation. (b) UVvisNIR absorbance spectra of SWNTs before and after
chirality separation. Under the same weight concentration, chirality-separated (6,5)-SWNTs oered >10-fold higher absorbance at 980 nm as
compared to those before separation. (c) NIR-II uorescent images of a mouse bearing a 4T1 tumor after injection with chirality-separated (6,5)-
SWNTs taken at 12, 24, and 48 h post injection, showing clear SWNT accumulation in the 4T1 tumor. The left image is a optical photo of this
mouse. (d and e) IR thermal images from 4T1 tumor bearing mice 48 h after injection with chirality-separated (6,5)-SWNTs (d) or as-made SWNTs
(e) after 5 min of 980 nm laser irradiation at a power density of 0.6 W/cm2. (f) The tumor temperature changes on dierent groups of mice under
980 nm laser irradiation. C18PMH-PEG coated SWNTs at the i.v. injection dose of 0.254 mg/kg of SWNTs were used in this study. Reprinted with
permission from ref 144. Copyright 2012 American Chemical Society.
specicity of molecular aptamers, and realized ecient and particles with gold nanostructures have been proposed by a
selective photothermal destruction of cancer cells.91 variety of groups. There have been two commonly used
2.1.6. Gold-Shelled Nanocomposites for Imaging- strategies to develop gold-based magnetic PTT agents, by
Guided Therapy. In the process of PTT, introducing imaging coating magnetic nanospheres by a layer of gold shell, or by
during therapy, or imaging-guided therapy, has been proposed attaching ultrasmall magnetic nanoparticles on gold nanostruc-
to improve the treatment eciency. First, the exact tumor tures such as AuNRs.92,94,95 Hyeon and co-workers proposed
location, size, and shape should be visualized by imaging to the combination of magnetic nanoparticles and AuNSs to
ensure that the whole tumor is eectively exposed to the light develop a novel nanomedical platform for diagnostic MR
during PTT treatment. Second, real-time tracking of the imaging and simultaneous PTT treatment92,93(Figure 9ae). In
photothermal agent after systemic administration by imaging their work, monodispersed 7 nm Fe3O4 nanoparticles stabilized
would allow us to carry out the laser irradiation at the right time with 2-bromo-2-methylpropionic acid (BMPA) were covalently
point when the photothermal agent reaches the highest attached to amino-modied silica spheres through a direct
accumulation in the tumor, so that the optimized therapeutic nucleophilic substitution reaction between the bromo groups
outcome could be achieved. Last, advanced imaging techniques and the amino groups. Au seed nanoparticles were attached to
would allow the monitoring of therapeutic responses after the residual amino groups of the silica spheres. Finally, a
treatment. Therefore, to aord the PTT agents more enriched complete Au shell with embedded Fe3O4 nanoparticles was
functionalities in imaging and therapy, many gold-based formed around the silica sphere by the seed-mediated growth,
nanocomposites have been developed by a large number of resulting in the formation of magnetic AuNSs (Mag-AuNSs).
research groups for imaging-guided PTT.9294 Anti-HER2/neu antibody was linked onto the surface of Mag-
Magnetic resonance (MR) imaging is one of the most AuNSs for targeted MR imaging and NIR PTT killing of
powerful imaging techniques currently used in the clinic. Many SKBR3 breast cancer cells. In a similar approach, Lee et al.
multifunctional nanocomposites by coupling magnetic nano- fabricated a multifunctional nanocomposite of Au shelled
Figure 15. Imaging-guided PTT for sentinel lymph node (SLN) ablation to inhibit tumor metastasis. (a) A scheme showing the design of animal
experiment. 4T1 murine breast tumor cells were subcutaneously injected on the right hind foot of each Balb/c mouse. Tumor cells would then
spread from the primary tumor to its nearby SLNs to form metastatic sites. (b) NIR-II uorescent imaging of a tumor-bearing mouse taken at
dierent time points after injection with SWNT-PEG. The retention of SWNTs in the SLN reached its peak level at 90 min postinjection. (c)
Morbidity-free survival of dierent groups of mice after various treatments indicated (7 mice per group). Reprinted with permission from ref 145.
Copyright 2014 John Wiley & Sons, Inc.
MnFe2O4 nanoparticles for synchronous MR imaging and outcomes (100% of tumor elimination after NIR laser
PTT.96 treatment) was achieved in our animal experiments.
To control the particle size, dispersivity, and reproducibility Upconversion nanoparticles (UCNPs), particularly lantha-
of the gold shell attached on the surface of the Fe3O4 nide-doped nanocrystals, which emit high-energy photons
nanoparticles, Shis group developed a simple but ecient under excitation by the NIR light, have found potential
route to construct a superparamagnetic Fe3O4 core/gold shell applications in many dierent elds including biomedi-
structured nanocomposite with tunable dimensions (100240 cine.99103 As compared to traditional down-conversion
nm in diameter)94(Figure 9fj), which could serve as a uorescence imaging, the NIR light excited upconversion
theranostic agent for MR imaging-guided PTT as demonstrated luminescence (UCL) imaging relying on UCNPs exhibits
in their in vivo experiments. The same group also designed improved tissue penetration depth, higher photochemical
uniform AuNRs-capped magnetic core/mesoporous silica shell stability, and free of autouorescence background, promising
nanoellipsoids (Au NRs-MMSNEs) by coating a uniform layer in biomedical imaging with high sensitivities.103105 Multifunc-
of AuNRs onto the outer surface of a magnetic core/ tional nanoparticles based on UCNPs have been also
synthesized and used for imaging-guided PTT. Our group
mesoporous silica shell nanostructure,97 based on a two-step
developed a novel class of multifunctional nanoparticles
chemical self-assembly process. The obtained multifunctional
(MFNPs) based on UCNPs with combined optical and
nanoellipsoids showed strong NIR absorbance and could also
magnetic properties useful in multimodality imaging and
be used for MR imaging-guided PTT. therapy102,106,107(Figure 11). Ultrasmall superparamagnetic
Recently, our group designed a multimodal imaging-guided, Fe3O4 nanoparticles (IONPs) were adsorbed on the surface
magnetic targeting enhanced photothermal ablation cancer of a NaYF4-based UCNP by electrostatic attraction, forming a
treatment strategy using Au shelled iron oxide nanoclusters98 UCNPIONP complex, on top of which a thin gold shell was
(Figure 10). Such composite nanoparticles with diameters of formed by the seed-induced reduction growth. Those UCNP@
100 nm exhibit strong magnetic property and high NIR IONP@Au MFNPs were successfully used for in vivo dual-
optical absorbance useful for both MR and PA imaging, modal imaging guided and magnetically targeted PTT, via a
respectively. Because of their rapid responses under local concept similar to that above-mentioned. Besides our design,
magnetic eld together with prolonged blood circulation time, Song and co-workers in a recent study fabricated silver-coated
such composite nanoparticles after iv injection could be UCNPs (UCNP@Ag) with NIR absorption, which were also
eectively attracted to the tumor, nearby which an external useful for UCL simultaneous optical imaging and photothermal
magnetic eld was applied. Because of the remarkably enhanced ablation of cancer cells.108 This class of coreshell nano-
tumor accumulation of nanoparticles as the result of magnetic particles is expected to be an attractive theranostic agent for
targeting, photothermal ablation with excellent therapeutic imaging-guided tumor ablation.
Figure 16. PEGylated nanographene oxide (NGO-PEG) for photothermal therapy. (a) A scheme of a NGO with PEG functionalization and Cy7
labeling. (b) An AFM image of NGO-PEG. Inset is a photo of NGO-PEG solution. (c) In vivo uorescence images of tumor bearing mice taken 24 h
post injection of Cy7 labeled NGO-PEG. Eective tumor uptake of NGO-PEG was observed in three dierent types of tumor models. (df) In vivo
PTT study using intravenously injected NGO-PEG. (d) Tumor growth curves in dierent groups of mice after various treatments indicated. The
tumor volumes were normalized to their initial sizes. (e) Survival curves of mice bearing 4T1 tumor after various treatments indicated. NGO-PEG
injected mice after PTT survived over 40 days without any single death. (f) Representative photos of mice after various treatments indicated.
Reprinted with permission from ref 157. Copyright 2010 American Chemical Society.
2.1.7. Toxicology Studies of Gold Nanomaterials. nanostructures, such as the particle size, concentration, and
Considering the nonbiodegradable nature of gold nanomateri- surface modication.
als, their long-term potential toxicity has become a concern Surface properties may be crucial in regulating the
when they are used for in vivo PTT cancer treatment. Although cytotoxicity of those gold nanoparticles. Connor et al. used
the standard methyl thiazolyl tetrazolium (MTT) assay to study
it is believed that gold is chemically inert, whether gold
the toxicity of 18 nm AuNPs with dierent surface coatings,110
nanomaterials would have any potential negative eect in including citrate, biotin, and CTAB. Citrate- and biotin-
biological systems still merits particular attention. Therefore, a modied AuNPs were not toxic even at a high concentration
large number of groups have spent substantial eorts to look of 250 M, whereas CTAB-coated nanoparticles showed
into the nanotoxicology of gold nanomaterials in vitro and in obvious toxicity at a low concentration of 0.05 M. However,
vivo.109 Many factors would aect the toxicity of the gold after being washed to remove free CTAB, the nanoparticles lost
Figure 17. Optimization of graphene-based photothermal agents. (a) AFM images of dierent graphene derivatives: while nGO-PEG and nRGO-
PEG showed similar ultrasmall sizes at about 2030 nm, the size of RGO-PEG was about 6070 nm. Insets are photos of the respective solutions.
RGO-PEG and nRGO-PEG showed much enhanced optical absorbance as compared to nGO-PEG. (b) The blood circulation of GO derivatives
measured by collecting blood from mice iv injected with 125I labeled nGO-PEG, nRGO-PEG, and RGO-PEG at various time points (n = 3). (c) The
biodistribution of GO derivatives in 4T1 tumor-bearing mice 2 days after injection. The radioactivities in tissue and blood samples were determined
by a gamma counter. (d) The 4T1 tumor growth curves of mice after various treatments indicated. The laser irradiation was conducted at the power
density of 0.15 W/cm2 for 5 min. (e) Survival of tumor-bearing mice after various treatments indicated. Reprinted with permission from ref 169.
Copyright 2012 Elsevier.
their toxicity, clearly suggesting that it was the coating AuNPs.114 Balb/C mice were intraperitoneally injected with 3,
molecules that resulted in the toxicity of AuNRs. 5, 8, 12, 17, 37, 50, and 100 nm Au NPs at a dose of 8 mg/kg/
Particle size was another important physical parameter week. It was found that the 3, 5, 50, and 100 nm AuNPs did not
controlling the behaviors of AuNPs in biological systems. Pan show harmful eects, while 837 nm AuNPs induced fatigue,
et al. examined the size-dependent toxicity of AuNPs in detail loss of appetite, change of fur color, and weight loss in mice.
by using several kinds of cell lines treated with Au atomic Recently, Danio rerio embryos have become a popular model
clusters of 0.8, 1.2, 1.4, and 1.8 nm, as well as 15 nm for toxicity experiments. Browning et al. showed that 11 nm
nanoparticles stabilized with triphenylphosphine derivatives.111 AuNPs could be passively transferred by diusion into the
According to the MTT assay data, the 1.4 nm Au clusters were chorionic space of the embryos and would retain their random-
the most toxic, while the 15 nm AuNPs were not cytotoxic even walk motion through chorionic space and into the inner mass
at concentrations 100-fold higher than the IC50 of the small of the embryos.115 Bar-Ilan et al. also obtained similar
clusters. Moreover, Chithrani and co-workers investigated the conclusions, based on experiments with 3, 10, 50, and 100
size-dependent cellular uptake of AuNPs by mammalian cells, nm Ag and Au nanoparticles.116 Whereas all sizes of Ag caused
and found that 50 nm AuNPs entered cells via receptor- toxicity in zebrash embryos, AuNPs appeared to be safe in
medicated endocytosis more eciently than smaller nano- their experiments.
particles.112 In a short summary, gold nanomaterials with dierent
Regarding in vivo toxicology, Cho et al. studied the in vivo morphologies have been widely explored as photothermal
toxicity of 13 nm PEG-coated AuNPs at the doses of 0.17, 0.85, agents, as illustrated by the many examples discussed above.
and 4.26 mg/kg in mice.113 After iv injection for 7 days, the The absorbance spectra of gold nanostructures could be easily
nanoparticles were found to be mainly accumulated in the liver tuned by their sizes, morphologies, as well as aggregation states,
and spleen, similar to that of the majority of nanomaterials after providing many opportunities to manipulate their photothermal
systemic administration. Recently, Chen et al. reported a performances in cancer ablation treatment. On one hand, gold
detailed study of the toxicity using various sizes of the is generally regarded as a rather inert element. On the other
Figure 18. Multimodal imaging and imaging guided PTT based on PEGylated RGO-iron oxide nanocomposites (RGO-IONP-PEG). (a) A scheme
showing the preparation of RGO-IONP-PEG from GO. (b) Cy5 labeled RGO-IONP-PEG could be used as a multifunctional imaging probe for
triple modal uorescence, MR, and photoacoustic imaging. (c) Using RGO-IONP-PEG as a photothermal agent, excellent in vivo tumor ablation
ecacy could be achieved. (d) After treatment, MR imaging was employed to monitor the therapeutic responses. Reprinted with permission from ref
177. Copyright 2012 John Wiley & Sons, Inc.
hand, it is clear that both surface chemistry and sizes of gold applications of CNTs, including the use of those 1D
nanomaterials would aect their behaviors and toxicology in nanomaterials for photothermal cancer treatment.131134
biological systems. Excitingly, some of those materials, such as Starting from 2005, PTT based on CNTs has been considered
AuNSs, have already entered the clinical trial. However, further as a noninvasive, harmless, and highly ecient therapeutic
in-depth investigations may still be necessary to understand the method using NIR laser irradiation. In 2005, Dai and co-
potential neglect eect, if any, of those nonbiodegradable gold workers developed DNA-coated single-walled carbon nano-
nanomaterials to biological systems at dierent levels. tubes (SWNTs) for in vitro cancer cell PTT. HeLa cells were
2.2. Carbon Nanomaterials for Photothermal Therapy incubated with DNA-CNTs and irradiated with 808 nm laser at
The sp2 carbon nanomaterials mainly including zero-dimen- the power density of 1.4 W/cm2 for 2 min, which induced
sional (0D) fullerenes, 1D carbon nanotubes (CNTs), and 2D remarkable cell death.135 By conjugating folate acid (FA) to
graphene have attracted a great deal of attention in various PEGylated SWNTs, they further demonstrated targeted
elds including biomedicine. In recent years, fullerenes, carbon photothermal destruction of FR positive cancer cells in vitro.
nanotubes (CNTs), and graphene have been developed as Since then, many dierent groups have studied CNT-based
nanocarries for drug delivery, as well as contrast probes for photothermal cancer cell killing, using various targeting peptide
biomedical imaging.117130 Because of their strong NIR optical or antibody conjugated CNTs as photothermal agents.136138
absorbance, CNTs and graphene have also been utilized as The in vivo PTT based on CNTs was rst reported by three
photothermal agents for cancer PTT treatment in vitro and in dierent groups at almost the same time in 2009. Moon et al.
vivo. uncovered that PEGylated SWNTs after intratumorally (i.t.)
2.2.1. Carbon Nanotubes. In the past years, there has injection into the tumor could oer strong photothermal eect
been a large amount of papers reporting the biomedical under irradiation by an 808 nm laser.139 It was found that
Figure 19. Freestanding palladium (Pd) nanosheets for photothermal therapy. (a) A TEM image of Pd nanosheets. Inset: Photograph of an ethanol
dispersion of the as-prepared Pt nanosheets in a curvette. (b) A high-resolution TEM (HRTEM) image of a Pt nanosheet at lying on the TEM grid.
(c) Selected area electron diraction (SAED) pattern of a single Pd nanosheet (shown in the inset). (d) A TEM image of stacked Pt nanosheets
perpendicular to the TEM grid. Inset: Thickness distribution of the Pd nanosheets. (ej) Optical absorption and photothermal properties of Pd
nanosheets. (e) Absorption spectra of hexagonal Pt nanosheets with average edge lengths of 21, 27, 41, and 51 nm. (f) Photothermal eect of
palladium nanosheets. (g) Viability of liver cells incubated for 48 h with dierent concentrations of Pt nanosheets. (h) Viability of human hepatoma
cells incubated with Pt nanosheets upon irradiation by an 808 nm laser with a power density of 1.4 W cm2 for various periods. (i and j) Micrographs
corresponding to 2 min (i) and 5 min (j) irradiation of cells in (h). Dead cells are stained with trypan blue. Scale bars = 50 m. Reprinted with
permission from ref 6. Copyright 2011 Nature Publishing Group.
carcinoma KB tumors were completely destroyed after 808 nm accumulation of nanotubes in the mouse skin. The optimized
laser irradiation at the power density of 76 W/cm3 for 3 min PEGylation that gave SWNTs a blood circulation half-life of
(Figure 12). Besides SWNTs, multiwalled carbon nanotubes 12 h was ideal in terms of balancing skin and tumor
(MWNTs) also exhibit strong NIR absorbance. Burke et al. accumulation of nanotubes (low skin but high tumor uptake).
injected MWNTs functionalized with pluoronic F127 (100 g The 4T1 murine breast cancer tumor-bear mice iv treated with
per mouse) into RENCA tumors, which were then ablated SWNTs with the optimized PEGylation showed remarkable
upon 1064 nm laser irradiation (3 W/cm2, 30 s).140 In another tumor ablation ecacy after laser irradiation at the power
paper, Ghosh et al. reported that DNA-encased MWNTs (100 density of 1 W/cm2 for 5 min (Figure 13b and c). Therefore,
L, 500 g/mL) after i.t. injected into PC3 xenograft tumors surface coating is highly important when SWNTs are used for
could also result in complete ablation of tumors after irradiation biomedical applications such as PTT cancer treatment.
by the 1064 nm laser at the power density of 2.5 W/cm2 for 70 SWNTs are not only useful as a photothermal agent for in
s.141 vivo tumor PTT, but also can be used as a photoluminescent
Despite the encouraging in vivo PTT therapeutic eects agent for in vivo tumor imaging. Dai and co-workers found that
realized in the above three reports, CNTs were directly injected
PEG-branched polymer and PEGylated phospholipid cofunc-
into tumors in those studies. Cancer treatment upon systemic
tionalized SWNTs showed long blood circulation and high
administration (e.g., iv injection) generally would have better
tumor uptake upon iv injection. Mice bearing 4T1 murine
clinical relevance. To achieve PTT using systemically injected
CNTs, the surface chemistry of nanotubes should be optimized breast tumors after iv injection with SWNTs at the dose of 3.6
to enable highly ecient tumor targeting. In a study by our mg/kg were imaged under 808 nm excitation with a low power
group, we synthesized a series of amphiphilic polymers by density at 0.15 W/cm2 during imaging. A lab-built photo-
anchoring polyethylene glycol (PEG) of dierent lengths at luminescence imaging setup was used to collect emitted light
various densities on poly(maleic anhydride-alt-1-octadecene) within the 1.01.4 m range, which was the NIR-II region as
(C18PMH), obtaining a small library of C18PMH-PEG dened by Dai and co-workers. Rather strong NIR-II
polymers to modify SWNTs142 (Figure 13a). While SWNTs uorescence signals were found in the tumors after iv injection
with insucient PEG coating would be rapidly cleared out from of SWNTs, indicating the ecient tumor accumulation of
the circulating blood into reticuloendothelial systems (RES) nanotubes. Next, those tumors were irradiated for 5 min at 0.6
with little tumor uptake, heavily PEGylated SWNTs showed W/cm2 with the 808 nm laser, which induced 100% tumor
signicantly increased blood circulation half-life and high tumor ablation.143 This work demonstrated the use of SWNTs as an
uptake after iv injection, but could result in substantial imagable photothermal agent for in vivo tumor PTT.
Figure 20. Hydrophilic ower-like CuS superstructures as an ecient photothermal agent for ablation of cancer cells. (a) Schematic representation
of a CuS superstructure serving as laser-cavity mirrors for 980 nm laser and its photothermal conversion. (b) The temperature elevation of aqueous
dispersions containing the CuS superstructures or their building blocks. (c) The temperature elevation of the aqueous dispersion of CuS
superstructures with dierent concentration as a function of irradiation time, and water was used as a control. Inset: Plot of temperature change
(T) over a period of 5 min versus CuS superstructure concentration. (d) The temperature elevation of the aqueous dispersion of CuS
superstructures (0.25 g L1) coated with the chicken skin as a function of irradiation time of 980 nm laser. The inset shows a photograph of the
measuring facility for recording temperature. Reprinted with permission from ref 8. Copyright 2011 John Wiley & Sons, Inc.
As-synthesized SWNTs normally contain a large number of 15c). This work demonstrates that imaging and ablation of
dierent chiralities, each with varied absorption wavelengths. SLNs with nanoagents could help to prevent cancer lymphatic
Therefore, in photothermal treatment when a NIR laser is used, metastasis, making photothermal therapy a potentially useful
only a small portion of SWNTs that are in resonance with the addition to surgery.
laser wavelength could be eectively heated. In a recent work 2.2.2. Nanographene. Motivated by the successes of using
by the same group, chirality enriched (6.5)-SWNTs with CNTs for biomedical applications, the 2D nanocarbon
resonance absorption at 980 nm and emission near 1200 nm graphene has also opened many new opportunities in
were separated by the gel ltration method and used for nanobiomedicine due to its unique physical and chemical
imaging-guided PTT (Figure 14). An extremely low dose of properties.146149 Since 2008, a large number of groups have
puried SWNTs at 0.16 mg/kg was used to achieve eective in reported graphene and graphene oxide (GO)-based biomedical
vivo tumor ablation, in marked contrast to the dose needed for applications including biosensing,150152 drug and gene
unsorted SWNTs (dose = 1.0 mg/kg).144 Remarkably lowering delivery,119,120,153156 bioimaging,5,157160 as well as tissue
the dose of photothermal agent used in PTT is greatly helpful engineering scaolds.161163 In recent years, motivated by its
to reduce the potential toxicity concern of using those light- high NIR absorbance, GO has also been explored as a new
absorbing nanomaterials for potential clinical applications. photothermal agent for PTT cancer treatment. In 2010, our
More than 90% of cancer deaths directly or indirectly group for the rst time studied the in vivo behaviors of
resulted from the metastatic spread of tumor cells. At the early PEGylated nano-GO (nGO-PEG) with uorescent labeling
stage of cancer metastasis, sentinel lymph nodes (SLNs) nearby (Figure 16). In this work, a NIR uorescent dye was conjugated
the primary tumor usually have the highest risk of being to nGO-PEG for in vivo uorescence imaging, which
invaded by metastasizing cancer cells. In our latest work, we for uncovered high tumor passive uptake of PEGylated nano-GO
the rst time used PEGylated SWNTs as the theranostic agent after iv injection in three dierent tumor modals. We then used
for imaging and photothermal ablation of metastatic SLNs in an nGO-PEG as a photothermal agent to generate heat with 808
animal tumor model145 (Figure 15a). By using NIR-II nm laser irradiation to kill tumors, resulting in 100% tumor
uorescent imaging, we clearly visualized the translocation of ablation at the laser power density of 2 W/cm2 with the nano-
SWNTs from the injected primary tumor to the nearby SLNs GO dose of 20 mg/kg.157 This was the rst report of using
(Figure 15b). Importantly, it was found that photothermal graphene materials for in vivo cancer PTT. Later, several
ablation of both primary tumors and SLNs could oer dierent groups have also studied GO-based PTT in vitro and
remarkably prolonged mouse survival as compared to mice in vivo.164166 There was a report suggesting that GO could
treated by elimination of only their primary tumors (Figure oer a stronger photothermal eect in comparison with CNTs
benecial for the treatment of relatively large tumors without

signicantly harming nearby normal tissues.
To enhance the therapeutic selectivity and realize active
tumor targeting, several groups have developed tumor-targeting
GO nanosheets for PTT. Dais group used noncovalently
PEGylated nano-RGO attached with a targeting peptide Arg-
Gly-Asp(RGD) for selective photothermal killing of U87MG
cancer cells in vitro.168 In another study, Akhavan et al. also
showed that an ultralow concentration (1 g/mL) of
PEGylated GO nanoribbons functionalized by RGD peptide
could be used for in vitro targeted PTT.166 Recently, the same
group developed an ecient in vivo photothermal agent using
RGD-functionalized RGO nanomeshes in a mouse model.170
By using TiO2 nanoparticles, rGO were transformed into GO
nanomeshes through photocatalytic degradation. GO nano-
meshes functionalized by PEG, RGD, and Cy7 then were
utilized for in vivo tumor targeting and uorescence imaging of
U87 tumors in mice. The rGO nanomeshes-PEG solution
exhibited 4.2- and 22.4-fold higher NIR absorption at 808 nm
than rGO-PEG and GO with sizes of 60 nm and 2 m,
respectively. The excellent NIR absorbance and tumor targeting
of rGO nanomeshes resulted in ultraecient PTT.
2.2.3. Carbon-Based Composite Nanostructures. To
oer carbon nanomaterials additional properties and functions,
various inorganic nanoparticles have been grown on the surface
of nanocarbons, yielding carbon-based nanocomposites for
dierent biomedical applications. In 2009, Kim et al. reported
Figure 21. Fe3O4@Cu2xS coreshell nanostructures for dual-modal that Au nanoparticles could be grown on the surface of CNTs
imaging and photothermal therapy. (a) Experimental design for the to yield Au coated CNTs (AuCNTs),171 which could not only
synthesis of Fe3O4@Cu2xS coreshell nanostructures. (b) Photo- be used as photoacoustic contrast agents for in vivo imaging,
graph of the tumor-bearing mouse (tumor was marked by a dashed but were also useful for potential individual cancer cell killing
circle). (c) An IR thermal image of the tumor-bearing mouse treated due to the photothermal eect. In our recent work, a layer of
with the Fe3O4@Cu2xS nanoparticles after a 980 nm laser irradiation AuNPs was in situ grown on the surface of DNA coated
for 2 min. The irradiated area was marked by a dashed circle. (d) The SWNTs, yielding SWNT-Au nanocomposite, which was then
temperature proles in regions 11 and 12 marked in (c) as a function coated with folic acid (FA) modied PEG.172 The obtained
of the irradiation time. (e and f) The representative HE images of ex
vivo tumor sections injected with water only (e) and an aqueous
SWNT-Au-FA nanocomposite could then serve as a strong
dispersion of polymer-modied Fe3O4@Cu2xS nanoparticles (Cu surface-enhanced Raman scattering (SERS) imaging probe to
content 50 ppm) (f), after photothermal ablation. Reprinted with detect FR positive cells. The dramatically enhanced NIR
permission from ref 202. Copyright 2013 American Chemical Society. absorbance of SWNT-Au also allowed us to use them for
targeted photothermal ablation of cancer cells with high FR
at the same concentration, although their results may need expression.
further explanation.167 Similar to studies with CNTs, a number of inorganic
To improve the GO-based PTT, GO could be chemically nanoparticles were also coupled with nanographene to endow
reduced into reduced graphene oxide (RGO), which showed the obtained nanocomposites more enriched functionalities.
much higher NIR absorbance as compared to GO.168,169 In a Recently, in two separated studies, uorescent Au nanoclusters
work by Dai and co-workers, a new type of ultrasmall RGO and quantum dots were conjugated to nanographene for drug
with high NIR absorbance was functionalized with PEG and delivery, uorescent bioimaging, and photothermal ther-
used for in vitro photothermal ablation of cancer cells.168 In a apy.173,174 Chen and co-workers reported a novel QD-tagged
later work by our group, we systematically compared the in vivo RGO nanocomposite combining the capability of bioimaging
behaviors of various GO derivatives with dierent surface with PTT.174 Interestingly, as the QD-RGO absorbed NIR
coatings and sizes using a radiolabeling method (Figure 17). irradiation to cause cell killing and PTT, the generated heat
We found that ultrasmall nano-RGO with noncovalent PEG from the QD-RGO simultaneously caused a temperature
coating showed relatively low RES accumulation and high increase and a marked decrease in the QD brightness, oering
tumor uptake. With 6-fold enhanced NIR absorbance and 8- a method for in situ heat/temperature sensing and a real-time
fold increased tumor uptake as compared to nGO-PEG, our indictor of the PTT progress.
newly developed nRGO-PEG was then used as a new Superparamagnetic iron oxide nanoparticles as a contrast
photothermal agent for in vivo cancer treatment. It was agent of MR imaging could also be grown on the surface of GO
uncovered that 4T1 breast cancer tumors grown on Balb/c to form magnetic GO-based nanocomposite, in which GO was
mice after iv injection with nRGO-PEG were completely usually partially reduced into RGO. Using their strong
ablated after the 808 nm laser irradiation at an ultralow power superparamagnetic properties, the obtained RGO-IONP after
density of 0.15 W/cm2 for 5 min.169 The laser power density PEGylation could be used for magnetically targeted drug
we used (0.15W/cm2) in this work is the lowest so far in delivery, MR imaging, and PTT cancer treatment.175178 In one
literature for in vivo PTT cancer treatment, and could be of our reports, an amphiphilic C18PMH-PEG polymer was
Figure 22. CuTe nanostructures for SERS used as SERS probes and photothermal agents in vitro. TEM images of dierent CuTe nanostructures:
(a) nanocubes, (b) nanoplates, and (c) nanorods. (d) UVvisNIR spectra of dierent CuTe nanostructures. (e) A scheme showing the use of
CuTe nanocubes as a SERS probe and a photothermal agent. Reprinted with permission from ref 205. Copyright 2013 American Chemical Society.
introduced to functionalize RGO-IONP nanocomposite to measurement, as well as in vivo MR imaging to determine the
render it great stability in physiological environments (Figure post-therapeutic response (Figure 18c and d). In our latest
18a). Utilizing the high NIR absorbance, strong super- work, a layer of gold was further grown on the surface of RGO-
paramagnetic property, as well as an extra uorescent label, IONP, yielding RGO-IONP-Au nanocomposite with strong
RGO-IONP-PEG could be used as a multifunctional nanop- superparamagnetism and eective X-ray absorbance, which
robe for in vivo multimodal PA, MR, and uorescence imaging, were useful for in vivo MR and X-ray dual-modal imaging,
respectively, all of which revealed high uptake of RGO-IONP- respectively. Moreover, because of the remarkably increased
PEG in 4T1 tumors after i.v. injection (Figure 18b). We then NIR absorbance oered by the Au layer, GO-IONP-Au could
carried out an in vivo PTT experiment. Mice bearing 4T1 be used as an enhanced photothermal agent for in vitro and in
tumors were iv injected with RGO-IONP-PEG at the dose of vivo cancer ablation.179 Therefore, graphene with the 2D
20 mg/kg and irradiated with 808 nm laser at the power density structure and large surface area oers plenty of room to
of 0.5 W/cm2 for 5 min. Highly ecient tumor ablation ecacy engineer a variety of multifunctional nanocomposites, promis-
was achieved, as evidenced by both caliper-based tumor size ing for cancer theranostic applications.
Like CNTs, GO without surface coating after intravenous

injection would mainly accumulate in the lung and induce
obvious pulmonary toxicity.190192 However, appropriate
surface functionalization would signicantly decrease the
pulmonary toxicity induced by GO. In a recent work, Multu
and co-workers193 found that while as-made GO without
surface coating resulted in severe and persistent lung injury,
pluronic functionalized GO with excellent dispersity exhibited
remarkably decreased lung toxicity without inducing obvious
inammation after inhalation, similar to their experimental
results related to CNTs.134
In our group, we have also systematically studied the in vivo
behaviors and toxicity of PEGylated GO and its derivatives via
dierent administration routes including oral feeding, intra-
Figure 23. PEGylated WS2 nanosheets as a multifunctional theranostic peritoneal (i.p.) injection, and iv injection. Radiolabeling was
agent for in vivo dual-modal CT/photoacoustic imaging guided used to study the in vivo behaviors of PEGylated GO and its
photothermal therapy. Reprinted with permission from ref 211. derivatives. 125I-labeled nGO-PEG via iv injection mainly
Copyright 2014 John Wiley & Sons, Inc. accumulated in the RES organs including liver and spleen.194
More importantly, we found that nGO-PEG via iv injection
could be gradually excreted from the mouse body via urine and
2.2.4. Toxicology Studies of Carbon Nanomaterials. feces, and did not obviously aect liver and kidney functions
Although carbon nanomaterials including CNTs and GO have within 3 months at a high dose (20 mg/kg). No appreciable
received considerable attention in biomedical applications, the damage or inammation was observed in examined major
safety of carbon nanomaterials in biological systems should be organs and tissues. Moreover, our group has also systematically
carefully examined. Numerous groups have deliberatively studied the in vivo behaviors and long-term toxicity of GO and
explored the toxicology of carbon nanomaterials, but PEGylated GO derivatives after oral and i.p. administration.195
conclusions seem to be somewhat controversial.180185 In It was shown that GO and PEGylated GO derivatives after oral
recent years, it has been widely acknowledged that the toxicity administration could not be absorbed by organs and were
of carbon nanomaterials to cells and animals could be closely rapidly excreted. In contrast, PEGylated GO derivatives, but
dependent on their surface chemistry, sizes, doses, and not uncoated GO, could be engulfed by phyagocytes in the RES
administration routes.186 system after i.p. administration by a size and surface
According to the literature, pristine CNTs without modication related manner. No signicant toxicity was noticed
appropriate surface functionalization have been shown to in our systematic serum biochemistry assay, complete blood
induce toxicity in various manners. However, when CNT are panel test, and histological analysis. Therefore, developing
properly functionalized (e.g., with biocompatible polymers such suitable surface coatings and controlling sizes are important to
as PEG), their toxicity could be dramatically reduced, to be the development of nanocarbon agents with low toxicity for
even not appreciable. In several early reports, pristine CNTs PTT applications.
without any surface coating after intratracheal instillation into Dierent from gold nanostructures, which usually exhibit
mice or rats187189 would induce severe pulmonary toxicity and well-dened absorbance peak or band, carbon nanotubes
inammation. On the other hand, in a recent work, Mutlu et al. (except chirality enriched SWNTs) and nanographene would
found that nanoscale dispersed SWNTs coated by Pluronic F show rather broad absorbance spectra all of the way from UV to
108NF after intratracheal instillation would be engulfed by NIR. Regarding their mass extinction coecient at the NIR
macrophages and gradually cleared over time, without showing wavelength, chirality enriched SWNTs is the highest, followed
obvious pulmonary toxicity.134 Thus, the pulmonary toxicity by noncovalently functionalized SWNTs without chirality
induced by CNTs is heavily dependent on the surface coating separation, RGO, and then GO. Those carbon nanomaterials
of CNTs. Moreover, the in vivo toxicity of CNTs after iv show rather high photothermal stability, better than typical gold
injection has also been reported by many groups. They found nanostructures (e.g., AuNRs, AuNCs), which could be melted
that well-functionalized nanotubes (e.g., PEG functionalization) under high-power photothermal heating and lose their NIR
after iv injection into mice mainly accumulated in liver and absorbance. The potential long-term toxicity of carbon
spleen, and would be gradually excreted via the biliary and renal nanomaterials, which again is closely associated with their
pathways, without inducing obvious toxicity.131,135 surface chemistry and sizes, has been under certain debate and
In addition to their surface coating, the length of CNTs also may be the main concern hampering their future clinical use.
plays an important role regarding the in vivo toxicity of
2.3. Other Inorganic Nanomaterials for Photothermal
nanotubes. Short CNTs may be easily enveloped by macro-
Therapy
phages, while long nanotubes may induce severe inammation
and DNA damage. In a work by Poland et al., it was found that 2.3.1. Pd Nanosheets. Besides Au and carbon nanoma-
long MWNTs (length 1050 m) without surface coating terials, which have been extensively explored in photothermal
intraperitoneally injected into the abdominal cavity of mice cancer treatment, a number of other inorganic nanomaterials
could induce inammation and the formation of lesions known with strong NIR absorbance have also shown promises as
as granulomas. However, shorter MWNTs (length 120 m) eective photothermal agents. Palladium (Pd) nanosheets
did not induce an obvious toxic eect.133 Therefore, the represent another class of noble-metal nanostructures with
toxicology of CNTs is obviously determined by the surface tunable LSPR peaks in the NIR region. In 2009, Zheng and co-
chemistry and sizes of nanotubes. workers reported the synthesis of freestanding hexagonal Pd
Figure 24. PEGylated WO3x nanowires as a new NIR photothermal agent for ecient ablation of cancer cells in vivo. (a and b) TEM (a) and
HRTEM (b) images of W18O49 nanowires. (c) UVvisNIR absorption spectrum of an aqueous dispersion containing 2 g/L W18O19 nanowires.
Inset: Photo of a aqueous dispersion. (d) Plots of the temperature within the irradiated tumor areas in two mice injected, respectively, with saline
solution and W18O19 nanowires solution (2 g/L), as a function of irradiation time. The inset is the corresponding full-body IR thermal image of these
two mice at 180 s. (e and f) H&E-stained histological images of the corresponding ex vivo tumor sections after laser irradiation for 10 min. Reprinted
with permission from ref 214. Copyright 2013 John Wiley & Sons, Inc.
nanosheets, which showed blue color and exhibited a well- positive charges on the sheet surface. As the result of the
dened and tunable surface plasmon resonance peak in the NIR enhanced cellular uptake, those silica-coated Pd nanosheets
region (Figure 19).6,196 Under the NIR laser (808 nm, 1 W) oered markedly enhanced photothermal cancer cell killing
irradiation, the temperature of the solution containing 27 ppm ecacy in vitro. The same group also fabricated silver-coated
Pd nanosheet rose from 28.0 to 48.7 C. In comparison, the Pd (Ag@Pd) coreshell nanoplates using uniform Pd nano-
temperature of the solution in the absence of Pd nanosheets sheets as the seeds.198 The bimetallic nanoplates exhibited
increased by only 0.5 C. As compared to Ag and Au tunable SPR properties over a wide spectral range and
nanostructures, their Pd nanosheets exhibited much improved outstanding photothermal stability. After being incubated with
photothermal stability, and could be used to induce a strong silica-coated Pd@Ag nanoplates, 100% of the liver cancer cells
photothermal eect to destruct cancer cells. were killed after 5 min irradiation with an 808 nm laser at a
The 2D ultrathin nature of the Pd nanosheets prevented power density of 1.4 W/cm2.
them from eective cell entry to certain extent. To promote 2.3.2. CuS Nanostructures. Copper sulde (CuS) nano-
cellular uptake of those nanosheets, Zheng and co-workers crystals as a kind of copper chalcogenide-based nanomaterials
altered the ultrathin feature of the Pd nanosheets by coating have been demonstrated to be a new type of photothermal
with silica197 to enlarge the sheet thickness and introduce therapeutic agent. Usually, CuS nanoparticles were synthesized
Figure 25. Indocyanine green (ICG) as near-infrared dual-functional targeting probes for optical imaging and photothermal therapy. (a) Self-
assembly process of ICG-PL-PEG probe and the subsequent antibody (mAb) conjugation. (b) Photograph of a mouse bearing U87-MG tumor. (c)
IR thermal images of mice bearing U87-MG tumors under dierent treatments. (d) Histological staining of the excised tumors 12 h after dierent
treatments indicated. Targeted photothermal therapy enabled by antibody conjugated ICG-PL-PEG probe resulted in signicant tumor cell damage
after laser ablation. Reprinted with permission from refs 216 and 225. Copyright 2011 and 2012 American Chemical Society.
by wet chemistry methods and had an optical absorption band However, one of the limitations of CuS nanoparticles as a
in the NIR range with a maximum absorbance at 9001000 photothermal agent was their relatively low photothermal
nm. Li and co-workers found that the aqueous solution of CuS conversion eciency. Hu and co-workers reported hydrophilic
nanoparticles under irradiation by a NIR laser beam at 808 nm ower-like CuS superstructures as an ecient 980 nm laser-
would show a rapid temperature increase.199 As the result, the driven photothermal agent for ablation of cancer cells8 (Figure
CuS nanoparticle-induced photothermal destruction of HeLa 20). The as-synthesized CuS superstructures exhibited a high
cells occurred in a laser dose- and nanoparticle concentration- NIR photothermal conversion eciency that was improved by
dependent manner, and displayed minimal dark cytotoxicity approximate 50% from that of their corresponding CuS
eect. The same group also synthesized and evaluated a novel nanoparticle building blocks. Under 980 nm illumination, the
chelator-free64Cu labeling method to radiolabel CuS nano- CuS nanoowers showed almost complete cell killing at a low
particles, obtaining64(Cu)CuS nanoparticles suitable for both power density (0.5 W/cm2) when incubated with HeLa cells.
positron emission tomography (PET) imaging and photo- Importantly, cancer cells in vivo can be eciently killed by the
thermal cancer treatment.7 Recently, they further demonstrated photothermal eect of CuS superstructures under the
that CuS nanoparticles could be used as a new class of irradiation of 980 nm laser using a conservative and safe
photoacoustic imaging contrast agent for deep tissue imaging power density at 0.51 W/cm2 over a short period time (510
under 1064 nm excitation,200 suggesting the great potential of min). However, it should be noted that the size of those CuS
using CuS nanoparticles for imaging guided PTT. superstructures at 1 m may be too large for in vivo use.
Figure 26. PEGylated nanoparticles encapsulating a nonuorescent NIR organic dye as a highly eective photothermal agent for in vivo cancer
therapy. (a) A scheme showing the structure of PEGylated nanomicelles containing IR825 dye molecules. (b) The blood circulation curves of IR825-
PEG and IR825-PEG-Cy5.5 after iv injection as determined by measuring either IR825 absorbance or Cy5.5 uorescence, respectively. (c) In vivo
uorescence images of a 4T1 tumor bearing Balb/c mouse taken at dierent time points post injection of IR825-PEG-Cy5.5. (d) IR thermal images
of 4T1 tumor-bear mice without (upper row) or with (lower row) iv injection IR825-PEG (10 mg/kg, 24 h p.i.) under the 808 nm laser irradiation
taken at dierent time intervals. (e) The growth of 4T1 tumors in dierent groups of mice after various treatments indicated. (f) Survival curves of
mice after various treatments as indicated in (e). Reprinted with permission from ref 14. Copyright 2013 John Wiley & Sons, Inc.
Therefore, the same group in a later work reported the et al. presented the integration of iron oxide nanoparticles with
development of hydrophilic Cu9S5 plate-like nanocrystals with a a CuS shell for the preparation of multifunctional Fe3O4@
mean size of 70 nm 13 nm as a novel photothermal Cu2xS coreshell nanoparticles202(Figure 21). This new class
agent.201 The aqueous dispersion of these Cu9S5 nanoplates of nanoparticles featured ultrasmall particle size, super-
exhibited an intense absorbance in the NIR, and its temperature paramagnetic property, low toxicity, and a highly ecient
could be increased by 15.1 C within 7 min under the photothermal eect. The tumors treated with the Fe3O4@
irradiation of 980 nm laser with a power density of 0.51 W/cm2 Cu2xS nanoparticles could be visualized by T2-weighted MR
due to the eective photothermal conversion. imaging, and showed typical signs of cell damage under a low-
Nanoparticles with combined optical and magnetic function- power density laser irradiation (0.6 W/cm2), such as cell
alities are important for biomedical applications. Recently, Tian shrinkage, loss of contact, and nuclear damage. Those results
metal dichalcogenides (TMDCs), such as MoS2, MoSe2, WS2,

and WSe2, all consist of a hexagonal layer of metal atoms (M)
sandwiched between two layers of chalcogen atoms (X) within
stoichiometry MX2. The common feature of these materials is
the layered structure with strong covalent bonding within each
layer and weak van der Waals forces between dierent MX2
layers. For their special characteristics, TMDCs have become
the rising star in recent years, oering great opportunities in
physics, chemistry, and materials science.206210 Chou et al. for
the rst time uncovered that MoS2 nanosheets could serve as a
new NIR photothermal agent, with approximately 7.8 times
greater NIR absorbance relative to GO on a per mass basis.10
Figure 27. A schematic illustration to show the formation of HSA- The extinction coecient of MoS2 nanosheets at 800 nm was
IR825 complex, as well as its unique optical behavior. HSA-IR825, 29.2 L/gcm, which was higher than that of AuNRs (13.9 L/g
which is prepared by simply mixing HSA and IR825, shows a high QY cm) and comparable to that of RGO (24.6 L/gcm). In another
under 600 nm excitation useful for uorescence imaging, together with
a low QY under 808 nm excitation ideal for photothermal therapy.
work, bismuth selenide (Bi2Se3) nanoplates were used as a
Reprinted with permission from ref 232. Copyright 2014 Elsevier. theranostic platform for simultaneous cancer imaging and
therapy upon local administration into tumors.9
Recently, our group developed a novel PTT agent based on
suggest the promise of developing a copper chalcogenide WS2 nanosheets for multimodal imaging and in vivo photo-
nanoplatform for cancer theranostic applications. thermal ablation of tumors in a mouse model211 (Figure 23).
There have been several other types of copper-containing Using the thiol chemistry method, the surface of WS2
NIR-absorbing nanomaterials developed for PTT cancer nanosheets was coated with PEG to acquire improved
treatment. Copper selenide nanocrystals (CuSe), similar to physiological stability and biocompatibility. Utilizing the strong
CuS nanoparticles, have also been explored for cancer imaging X-ray attenuation ability and high NIR optical absorbance of
and PTT.199,203 Hessel et al. synthesized Cu2xSe nanocrystals WS2, we were able to image tumors by X-ray computed
with an average diameter of 16 nm and an intense NIR tomography (CT) and photoacoustic tomography, respectively.
absorbance peak, which enabled signicant photothermal Highly eective in vivo photothermal ablation of tumors under
heating to kill cancer cells in vitro under laser irradiation.204 NIR laser was then realized, after either intratumoral injection
Recently, Li et al. reported a procedure to prepare highly with a low dose of WS2-PEG or intravenous injection with a
monodispersed CuTe nanocubes, nanoplates, and nanorods moderate dose of this nanoagent into 4T1 tumor-bearing mice.
based on the reaction of a copper salt with trioctylphosphine In another latest report by our group, we found that two-
telluride in the presence of lithium bis(trimethylsilyl) amide dimensional MoS2-PEG nanosheets could not only be utilized
and oleylamine205 (Figure 22). It was found that CuTe as a photothermal agent, but also act as a drug delivery carrier
nanocubes, in particular, displayed a strong NIR optical to load various types of aromatic drug molecules with high
absorption associated with localized surface plasmon resonance. loading capacities, enabling combined photothermal + chemo-
The preliminary results showed that those CuTe nanocubes therapy both in vitro and in vivo.212
could be used as SERS probes as well as photothermal agents. Besides transition metal suldes, transition metal oxides are
2.3.3. Other Inorganic Photothermal Nanoagents. also interesting candidates with LSPR properties. Among them,
There have been other types of inorganic nanomaterials also tungsten oxide (WO3x) nanocrystals are of great interest
showing great potential as photothermal agents. Transition- because of their strong NIR absorbance.213 In a recent work,
Figure 28. Convertible organic nanoparticles for NIR photothermal ablation of cancer cells. Polyaniline nanoparticles with visible absorbance at their
native EB state would be converted into the ES state with NIR absorbance in the presence of intracellular acidic or oxidative conditions, useful for
photothermal ablation of cancer cells. Reprinted with permission from ref 236. Copyright 2011 John Wiley & Sons, Inc.

Figure 29. Polypyrrole (PPy) organic nanoparticles for in vitro photothermal therapy. (a) Schematic to illustrate the synthesis of PVA-coated PPy
nanoparticles. (b) IR thermal images of 4T1 tumor-bearing mice i.t. injected with PPy nanoparticles exposed to the 808 nm laser at dierent power
densities. (c) Change of tumor temperatures on mice i.t. injected with PPy nanoparticles under the 808 nm laser irradiation at dierent power
densities. (d) Tumor growth in dierent groups of mice after various treatments indicated. A low laser power density at 0.25 W/cm2 was sucient to
induce complete tumor ablation. Reprinted with permission from ref 11. Copyright 2012 John Wiley & Sons, Inc.
Chen et al. reported the preparation of ultrathin PEGylated photothermal conversion eciency in the NIR region, those PB
W18O19 nanowires by a simple solvothermal route214(Figure nanoparticles could rapidly and eciently convert the 808 nm
24). The nanowires exhibited strong NIR absorption and could laser energy into thermal energy, and the photothermal stability
be used as a 980 nm laser-driven photothermal agent for the of PB nanoparticles was much higher as compared to other
ecient photothermal ablation of cancer. However, whether photothermal agents. All of those results demonstrated that PB
and how those metal suldes or metal oxides containing heavy nanoparticles could act as a promising photothermal agent for
elements (e.g., W, Mo, Bi) would be degraded, excreted, and do PTT treatment of cancers.
any long-term harmful eects require further systematic In a short summary, a wide range of inorganic nanomaterials
investigations. with high absorbance in the NIR have been extensively used in
Another inorganic PTT agent was Prussian blue (PB) PTT, showing encouraging therapeutic results both in vitro and
nanoparticles.215 Prussian blue, as an ancient dye, has been in vivo. However, most of these inorganic PTT agents are
approved by the US FDA for the treatment of radioactive nonbiodegradable and usually would retain in the body for long
exposure and demonstrated good biosafety in the human body periods, raising concerns regarding their potential long-term
based on sucient clinical trials. The PB nanoparticles were toxicity. Before these therapeutic strategies are tested in cancer
simply synthesized by mixing aqueous solutions of FeCl3 and patients, much more eort should be focused on the in vivo
K4(Fe(CN)6) in the presence of citric acid, which acted as the behaviors of those inorganic nanomaterials, including their
surface capping agent to prevent PB nanoparticles from pharmacodynamics, pharmacokinetics, and potential long-term
aggregation and mediate the size of PB nanoparticles.215 toxicity. Moreover, it would be interesting and important to
Because of the high molar extinction coecient and good compare the above-mentioned various dierent PTT agents
Figure 30. PEDOT:PSS organic stealth nanoparticles for in vivo photothermal therapy of cancer. (a) A scheme showing the fabrication process of
PEGylated PEDOT:PSS nanoparticles (PEDOT:PSS-PEG). (b) UVvisNIR spectra of PEDOT:PSS and PEDOT:PSS-PEG solutions at the
concentration of 0.02 mg/mL. Inset: A photo of PEDOT:PSS (left) and PEDOT:PSS-PEG (right) solutions at the concentration of 0.1 mg/mL in
water. (c) The heating curves of pure water and PEDOT:PSS-PEG (0.1 mg/mL) under 808 nm laser irradiation at a power density of 1 W/cm2. (d)
The growth of 4T1 tumors in dierent groups of mice after treatment. (e) Survival curves of mice after various treatments as indicated in (d). (f)
Representative photos of a PEDOT:PSS-PEG injected mouse at day 0 before PTT treatment and at day 10 after treatment. In the in vivo treatment
study, PEDOT:PSS-PEG at a dose of 10 mg/kg was iv injected into mice. Reprinted with permission from ref 12. Copyright 2012 American
Chemical Society.
side-by-side, to tell the advantages and limitations of each cancer treatment due to the potential long-term toxicity
agent, as well as identify the most promising ones with high concern. Recently, signicant attention has been paid to the
photothermal conversion eciency, optimized in vivo behav- development of NIR-absorbing organic materials as photo-
iors, and minimal long-term toxicity. thermal agents in PTT cancer treatment.
2.4. Organic Nanoparticles for Photothermal Therapy 2.4.1. NIR-Absorbing Dye Containing Nanocom-
plexes. Organic dyes with high quantum yields (QY) are
As discussed in the above section, a variety of NIR-absorbing generally preferred in uorescent optical imaging. However,
inorganic nanomaterials have been widely explored by many their photothermal eciency could be low because a part or
research groups as photothermal agents, showing high ecacies even a majority of the absorbed optical energy is emitted from
for PTT treatment of cancers in many preclinical animal those dye molecules as uorescence instead of heat. Organic
experiments. However, most of these currently used inorganic dyes with high NIR absorption coecients but low QYs, on the
photothermal agents, some of which even contain heavy metal other hand, may oer the best photothermal eciency because
elements, are nonbiodegradable and would retain in the body the thermal eect would prevail in the energy dissipation
for long periods, hampering their further applications in clinical process of those molecules after light excitation.
Figure 31. Porphysome nanovesicles generated by bilayers of porphyrin-conjugated phospholipids as a multimodal biophotonic theranostic agent.
(a) Schematic representation of a pyropheophorbide-lipid porphysome. (b) TEM images of negatively stained porphysomes containing 5% PEG-
lipid and 95% pyropheophorbide-lipid. Reprinted with permission from ref 13. Copyright 2011 Nature Publishing Group.
Among various organic dyes, indocyanine green (ICG) has thermal ablation of U87MG tumors after treatment with the
been approved by the federal drug administration (FDA) for a 808 nm NIR light (2 W/cm2, 10 min)225(Figure 25bd), in
number of clinical applications.216220 Besides being used in comparison to free ICG at the same dose.
uorescent imaging, ICG is also under investigation as a PTT With a similar structure of ICG, heptamenthine near-infrared
agent.216 However, several physicochemical characteristics, such dye has also been used as an NIR imaging probe.226228 Luo et
as concentration-dependent aggregation, poor aqueous stability, al. recently reported the chemical synthesis and biological
nonspecic binding to proteins, and lack of target specicity, characterization of a new heptamethine dye (IR808 DB),229
have limited the applications of ICG.221 All of these drawbacks natively with multifunctional characteristics of cancer targeting,
lead to a fast degradation in aqueous media and quick clearance near-infrared uorescence imaging, and ecient photothermal
from the body with a short half-life about 24 min. To improve anticancer activity. Peng et al. synthesized a multifunctional
the molecular instability of ICG and/or prolong its plasma half- micelle containing an 188Re-labeled radionucleotide for single-
life, the colloidal carriers such as poly(lactic-co-glycoloc acid) photon emission computed tomography (SPECT) imaging and
(PLGA), dextran, and nanoparticles assembled capsules have a IR-780 iodide NIR dye for uorescent imaging and PTT.230
been used to stabilize ICG and increase its blood circulation Their results showed that 188Re-labeled IR-780 injected into
time.220,222224 Yu et al. assembled a nanoparticle capsule lled HCT-116 tumors and treated with NIR light resulted in 82.6%
with ICG and coated it with anti-EGFR to target and induce of tumor growth inhibition 27 days after treatment.
photothermal ablation of 1483 squamous carcinoma cells in In our recent work, we synthesized a NIR-absorbing
vitro.218 Signicant thermal toxicity was observed for heptamethine indocyanine dye, IR825, which showed a super
encapsulated ICG as compared to free ICG under 808 nm high NIR absorption peak at 825 nm and a rather low QY
laser irradiation at a power density of 6 W/cm2. Zheng et al. (<0.1%)14,231 (Figure 26). A PEG grafted amphiphilic polymer
designed a novel ICG-containing nanostructure utilizing the was used to solubilize IR825, forming IR825-PEG micelle
noncovalent self-assembly chemistry between phospholipid- nanoparticles with great solubility and stability in physiological
polyethylene glycol (PL-PEG) and ICG216(Figure 25a). The solutions. As compared to ICG, IR825-PEG exhibited stronger
average diameter of ICG-PL-PEG nanoprobe was 17.6 nm. photothermal eect under 808 nm NIR laser irradiation, and,
Two representative targeting molecules, folic acid (FA) and more importantly, dramatically improved photothermal stabil-
integrin v3 monoclonal antibody (mAb), were conjugated to ity. Without showing any appreciable toxicity to cells, IR825-
the surface of the ICG-PL-PEG nanoprobe. It was shown that PEG nanoparticles could serve as an eective photothermal
the ICG-PL-PEG-mAb nanoprobe could photothermally ablate agent to destruct cancer cells under NIR light. In vivo animal
75% of U87MG human glioblastoma cells in vitro under the experiments uncovered the ultralong blood circulation half-life
808 nm NIR stimulation for 5 min at 2.25 W/cm2. Further in of IR825-PEG nanoparticles. As the result, highly ecient
vivo studies uncovered that ICG-PL-PEG-mAb after iv passive tumor accumulation of IR825-PEG was observed, due
injection into nude mice demonstrated more ecient photo- to the enhanced permeability and retention (EPR) eect of
Figure 32. Porphyrin nanodiscs for photothermal therapy and photodiagnostic applications. (a) Detergent dialysis procedure used to prepare
porphyrin nanodiscs. An ApoA-1 protein was induced to stabilize the edges of those nanodiscs. (b) Fluorescence emission of nanodiscs in the intact
(blue) versus the disrupted (red) state. (c) Singlet oxygen generation upon light irradiation (660 nm; 1.7 mW/cm2) of nanodiscs (1 M) in the
intact (blue) versus the Triton X-100 disrupted (red) state, as reported by the singlet oxygen sensor (6 M). (d) Nanodisc uptake in a model CHO
cell line expressing (left) and not expressing (right) SRBI, a receptor that interacts with ApoA-1. The scale bars represent 20 m. (e) Eect of
nanodisc concentration on light (660 nm; 1.7 mW/cm2)-induced phototoxicity for SRBI+ (red) and SRBI (blue) cells. Reprinted with permission
from ref 243. Copyright 2013 American Chemical Society.
cancerous tumors. The iv injection of IR825-PEG nanoparticles serum albumin (HSA), obtaining a HSA-IR825 nanocomplex
followed by NIR laser irradiation of tumors (808 nm, 0.5 W/ with separated imaging and therapy wavelength channels for
cm2, 5 min) oered an excellent therapeutic ecacy with 100% imaging-guided photothermal therapy232 (Figure 27). Interest-
of tumor destruction. Moreover, no obvious signal of toxicity ingly, the HSA-IR825 complex showed strong uorescence
was observed on IR825-PEG injected mice as evidenced by under 600 nm excitation with a high QY at 42%, useful for in
both hemological and histological data. This work presents a vivo uorescence imaging. Meanwhile, our HSA-IR825
new photothermal agent based on micelles of an NIR-absorbing complex exhibited another rather high absorbance peak at
organic dye for safe and highly eective photothermal cancer 820 nm, under excitation by which wavelength of the
treatment. uorescence QY was as low as 0.33%, ideal for eective
As mentioned before, the requirements for uorescent photothermal conversion in PTT cancer treatment. While HSA
imaging (a high QY for brighter signals) and PTT agent (a is the most abundant human protein, IR825 in this formulation
low QY for ecient photothermal conversion) are contro- after iv injection could be rapidly excreted by renal clearance.
versial. In our latest report, we developed a novel yet simple Such protein-based photothermal agent may have great
proteindye complex by binding IR825 molecule with human potential for future clinical translation.
Figure 33. Compare photodynamic therapy with photothermal therapy using self-quenched porphysome nanoparticles. (a) Schematic illustration of
the study rationale and design. (b) Generation of acute hypoxia/hyperoxia for xenograft tumors. (c) Tumor growth in each laser irradiation group.
Data expressed as mean standard deviation (SD) (n = 5). While photofrin-induced PDT was only eective for hyperoxia but not hypoxia tumors,
porphysome-induced PTT was eective under both conditions. Reprinted with permission from ref 244. Copyright 2013 American Chemical
Society.
2.4.2. NIR-Absorbing Conjugated Polymers. Conduc- Polypyrrole (PPy), an organic conductive polymer, has been
tive polymers usually with conjugated molecular structures have extensively used in organic electronics due to its high
been widely used in many dierent areas for applications such conductivity and outstanding stability. In addition, in vivo
as organic conductors, organic solar cells, eld-eect transistors, studies have conrmed that PPy has good biocompatibility and
and electroluminescence diodes.233235 Because of the high low long-term cytotoxicity.239,240 In 2011, PPy nanoparticles
NIR absorbance of many of those polymers, recently a number were used by Armes et al. as a contrast agent for optical
of groups have explored the potential use of conjugated coherence tomography (OCT),241 signicantly improving
polymers for photothermal cancer treatment.11,236238 In 2011, OCT imaging sensitively and facilitating the early stage
Yang et al. demonstrated the feasibility of a novel organic detection of cancers. Motivated by results in this report, our
photothermal agent based on polyaniline for the induction of group starting from 2012 has explored the use of PPy
nanoparticles as novel photothermal agents, taking advantages
hyperthermia in epithelial cancer236 (Figure 28). Polyaniline is
of their strong NIR absorbance11 (Figure 29). It was found that
biocompatible and has been used as an electroactive material to
the PPy nanoparticles coated with poly(vinyl alcohol) (PVA)
study cellular proliferation. During the doping process, the exhibited great photostability without any signicant decrease
optical-absorbance peak of polyaniline could be red-shifted in optical absorbance even after laser exposure for a long time,
toward the NIR region as a result of its transition from the in marked contrast to gold nanostructures. Following intra-
emeralidine base (EB) to the emeralidine salt (ES). The tumoral injection of PPy nanoparticles, excellent tumor
photothermal eciency of the polyaniline ES nanoparticles was treatment ecacy was realized using an ultralow power of
evaluated under NIR stimulation with epithelial A431 NIR laser irradiation at 0.25 W/cm2, achieving 100% tumor
carcinoma cells using 808 nm laser (2.45 W/cm2, 5 min), elimination. After PTT ablation, both liver and kidney function
showing a highly eective and feasible photothermal ablation makers were measured to be normal, suggesting no obvious
eect both in vitro and in vivo. hepatic and kidney disorder of mice induced by PPy treatment.
Figure 34. Dopamine-melanin colloidal nanospheres (Dpa-melanin CNSs) as an ecient NIR photothermal agent. (a) A SEM image of Dpa-
melanin CNSs. (b) UVvisNIR absorption spectra of dopamine and Dpa-melanin CNSs. (c) A digital photo of the 4T1 cell culture dish after
incubation with Dpa-melanin CNSs. The red circle shows the laser spot. (df) Confocal images of calcein AM (green, live cells) and PI (red, dead
cells) costained 4T1 cells after laser irradiation. (g) Cell viability of 4T1 cells after incubation with increased concentrations of Dpa-melanin CNSs.
(h) Cell viability of 4T1 cells treated with dierent concentrations of Dpa-melanin CNSs and laser irradiation (808 nm, 2 W/cm2, 5 min). Reprinted
with permission from ref 246. Copyright 2013 John Wiley & Sons, Inc.
A complete blood panel was carried out, and all parameters tumors reached 60 C after laser irradiation. All irradiated
were found to be normal. Therefore, the PPy-based in vivo tumors on mice injected with PPy nanoparticles disappeared 1
photothermal treatment of cancer induced no signicant side day after treatment, and no tumor regrowth was noted in this
eect to the treated mice. treatment over a course of 60 days.
A number of other groups have also used PPy as a Poly(ethylenedioxythiophene):poly(4-styrenesulfonate) (PE-
photothermal agent in their studies.237,242 Recently, Chen et DOT:PSS) nanoparticles are another class of conjugated
al. synthesized PPy nanoparticles via aqueous dispersion polymer nanoparticles utilized for photothermal ablation of
polymerization using FeCl3 as an oxidation agent and cancer cells reported by our group.12 We synthesized
poly(vinylpyrrolidone) as a capping agent.242 The photo- PEGylated PEDOT:PSS via a layer-by-layer (LBL) self-
thermal conversion eciency of PPy nanoparticles was assembly approach (Figure 30). The obtained PEDOT:PSS-
calculated to be 44.7%, which was relatively high as compared PEG nanoparticles with an average diameter of 80 nm showed
to those of previously reported materials. After iv injection with strong absorbance in the NIR and were highly stable in the
PPy nanoparticles (a dose of 10 mg/mL) for 24 h, the tumors physiological environment. Those PEDOT:PSS-PEG nano-
on mice were exposed to the 808 nm laser with a power density particles exhibited a stealth-like behavior with a long second
of 1 w/cm2 for 5 min, and the surface temperature of the phase blood circulation half-life of 21.4 3.1 h, which enabled
Table 2. A Summary of Functional Nanomaterials Developed for Combination Therapy

references
photothermally enhanced drug delivery FeCo/graphitic carbon shell 256,290
nanographene 123,291,293
plasmonic nanobublles 294297
photothermal-chemotherapy Au nanoparticles 51,283,302
Au nanorods 275,276,282303307,309,310
Au nanoshells 257,262,263,265,311314,318321
nanographene 123,164,277,291,321
CuS nanostructures 280,322,323
Pd nanosheets 196,197,279
indocyanine green nanoparticles 326
PEDOT:PSS nanoparticles 324
polypyrrole nanoparticles 325
photodynamic-chemotherapy N-(2-hydroxypropyl)methacrylamide 444
chlorin-core diblock methoxy micelle 448
methylene blue 449
silica nanocages 451
nanographene 450
photodynamic-photothermal therapy nanographene 454456
Au nanorods 457
carbon nanohorns 458
Au nanoowers 453,459,460
Au vesicle 56
Au nanocages 461
hollow silica nanoparticles 462
an extremely high tumor accumulation due to the EPR eect of and co-workers synthesized activable porphyrin nanodiscs by
cancerous tumors. PTT was carried out in mice bearing 4T1 complexing apolipoproteins to porphyrin-lipid using the
tumors. After iv injection of PEDOT:PSS-PEG nanoparticles (1 detergent dialysis method243 (Figure 32). The nanodiscs
mg/mL, 200 L) for 48 h, the tumor-bearing mice were treated varying from 1030 nm in size had a disc-like morphology.
with NIR light (0.5 W/cm2, 5 min), which was able to Fluorescence measurements of these nanodiscs in a detergent
completely eradicate the tumors on those treated mice. We also showed that uorescence was over 99% quenched in the intact
studied the potential toxicology of PEDOT:PSS-PEG in vivo. state with a 12-fold increase in singlet oxygen generation upon
Serum biochemistry assay and complete blood panel test were disruption. Those nanodiscs were found to display a 5-fold
carried on PEDOT:PSS-PEG injected (10 mg/kg) healthy increase in diusion coecient when compared to laser
Balb/C mice at days 7 and 40 post injection. All measured porphysomes. The ability to incorporate large amounts of
parameters fell within normal ranges, evidencing that photosensitizer molecules into such a compact structure
PEDOT:PSS-PEG nanoparticles were not noticeably toxic in allowed for phototherapeutic action, uorescence diagnostic
vivo to mice at our tested dose. applications, and the potential to eectively deliver photo-
2.4.3. Porphysomes. Porphyrin-lipid nanodevices or sensitizers deep into poorly permeable tumors.
porphysomes developed by Zheng and co-workers have also Recently, the Zheng group further compared photodynamic
shown great potential in photothermal cancer treatment
therapy (PDT) and PTT using matched light doses and
recently13 (Figure 31). Porphysomes, which were organic
matched porphyrin photosensitizer doses (with the photo-
nanoparticles self-assembled from phospholipidporphyrin
sensitizer being eective for either PTT or PDT based on the
conjugates, exhibited liposome-like structure, high porphyrin
existence of nanostructure)244(Figure 33). Using a novel
loading capacity, strong absorption of red and NIR light,
structure-dependent uorescence quenching, and excellent hypoxia tumor model, they demonstrated that while porphyr-
biocompatibility, promising for diverse biophotonic applica- in-based PDT was only eective for hyperoxia tumors and
tions. Porphysomes were enzymatically biodegradable and ineective for oxygen-lacking tumors, porphysomes-based PTT
induced minimal acute toxicity in mice with an extremely high was eective at both hyperoxia and hypoxic conditions, ideal for
intravenous dose of 1000 mg/kg. Following systemic eective ablation of solid tumors.
administration, prophysomes accumulated in tumors of Imaging capabilities could also be incorporated into
xenograft-bearing mice, which could be eectively cured after porphysome systems for imaging-guided therapy. In another
laser irradiation induced photothermal tumor ablation. interesting study again by this group, porphysomes were
The porphyrin nanovesicles with the size of 100 nm labeled with 64Cu for in vivo positron emission tomography
exhibited uorescence quenching and photothermal properties. (PET) imaging.245 The direct 64Cu labeling of porphysomes
Recent studies have shown that nanoparticles less than 40 nm was fast, simple, and exible. The reaction yield for the 64Cu-
may be more eective at penetrating deeply into brous tumors labeling of porphysomes was greater than 98%. Similar to many
than their large counterparts. Attempts to create smaller other nanoparticles, porphysomes were cleared through the
liposome vesicles remain a great challenge due to the growing hepatobilliary route, thus resulting in high accumulation within
instability as a result of the surface curvature. Recently, Zheng the liver and spleen and little to none in the bladder.
Figure 35. Au nanocages (AuNCs) covered by smart polymers for controlled release induced by NIR light. (a) Schematic illustrating how the system
works. (b) Atom-transfer radical polymerization of NIPAAm and AAm monomers (at a molar ratio of m = n) as initiated by a disulde initiator and
in the presence of a Cu(I) catalyst. (c) TEM images of AuNCs for which the surface was covered by a pNIPAAm-co-pAAm copolymer with a phase
transition temperature at 39 C. The inset shows a magnied TEM image of the corner of such a nanocage. (df) Absorption spectra of alizarin-
PEG released from the copolymer-covered AuNCs by heating at 42 C for 1, 3, 5, and 10 min (d); by exposure to a pulsed NIR laser at a power
density of 10 mW/cm2 for 1, 2, 4, 8, and 16 min (e); and by exposure to the NIR laser for 2 min at 10, 25, and 40 mW/cm2 (f). The insets show the
concentrations of released alizarin-PEG from the nanocages under dierent conditions. Reprinted with permission from ref 274. Copyright 2009
Nature Publishing Group.
2.4.4. Other NIR-Absorbing Organic Nanoparticles. PTT agent based on dopamine-melanin colloidal nanospheres
Some other organic nanomaterials have also been developed in (Dpa-melanin CNSs) with an average diameter of approx-
recent years as photothermal agents. Melanin is a well-known imately 160 nm for in vivo cancer therapy246 (Figure 34).
biopolymer widely distributed in almost all living organisms Similar to porphysomes, Dpa-melanin CNSs were completely
and has many distinct functions, such as the protection of composed of naturally occurring Dpa-melanin, yet could be
humans and animals from ultraviolet injury, antibiotic easily produced via a simple and cost-eective strategy. Those
functions, and quenching of free radicals. Moreover, its nanoparticles with high photothermal conversion eciency
absorption can be extended to the NIR region, making it showed good biodegradability, a high median lethal dose, and
useful in photothermal applications. Liu et al. presented a novel did not induce long-term toxicity during their retention in rats.
Figure 36. Mesoporous silica-coated graphene nanosheets for chemo-photothermal synergistic targeted therapy of glioma. (a) Design of DOX
loaded targeted peptide modied mesoporous silica-coated graphene nanosheets (GSPID) as a multifunctional drug delivery system for combined
chemo-photothermal targeted therapy of glioma. (b) Cumulative release proles of DOX from GSPID at dierent pHs with 6 W/cm2 NIR
irradiation. (c) Cell viability proles of glioma cells under dierent treatments as a function of graphene sheet concentrations. Reprinted with
permission from ref 277. Copyright 2013 American Chemical Society.
Moreover, the Dpa-melanin CNSs could be easily attached to with other therapeutic strategies, especially chemotherapy, has
other functional molecules, and thus could be a particularly thus received tremendous interest in recent years (Table
useful platform for simultaneous diagnosis and ecient 2).254259 In this section, we will rst introduce two commonly
treatment of cancer. employed mechanisms of using photothermal eect to promote
Overall, NIR-absorbing organic nanomaterials are encourag- chemotherapy, and then discuss various types of nanomaterials
ing alternatives of inorganic nanomaterials for applications in used in photothermal combination therapy.
PTT. Some organic agents (ICG) have already been approved 2.5.1. Light-Controllable Drug Release Based on the
by FDA for clinical applications. Dierent from NIR-absorbing Photothermal Eect of Nanocarriers. As discussed in detail
inorganic nanomaterials, which would retain in the body for above, the highly ecient photothermal conversion ability of
long periods of time, small organic dyes should be able to be various NIR-absorbing nanomaterials has been intensively
easily cleared out from the body with little long-term retention. explored for the PTT of cancer.258,260 Apart from being
Porphysomes solely containing biocompatible and biodegrad- directly utilized for photothermal ablation of cancer, the
able molecules are also safe agents promising for clinical use. photothermal eect of NIR-absorbing nanomaterials has also
However, the other organic nanoparticles, such as conjugated been exploited for remotely controlled drug release.261264 In
polymers, still need more investigations to understand their 2005, Kotaidis et al. found that gold nanoparticle solutions
potential biodegradation behaviors in vivo. under the ultrafast laser excitation at an optimal power density
2.5. Combination of Photothermal Therapy with Other would generate strong nonequilibrium heating between the
Therapeutic Approaches AuNPs and the peripheral water shell, which would contribute
Numerous preclinical and clinical studies have suggested that to the formation of the vapor bubble with a nanometer spatial
monotherapy (e.g., chemotherapy, radiotherapy, surgery, and scale and subnanosecond time scale.265,266 By utilizing these
some other therapeutics) is not as eective as we transient nanobubbles, various interesting laser triggered drug
expected.247249 What makes monotherapy ineective for release systems based on AuNPs loaded liposomes, polyelec-
cancer treatment could be attributed to the metastasis of trolyte capsules, and even red blood cells have been
cancer, development of drug resistance, individual dierences in demonstrated.267273 Besides, several recent studies have
cancer patients, and so on.250252 Combination therapy, which utilized thermosensitive polymers decorated AuNCs or
uses more than one therapeutic approach, has shown great AuNRs for drug loading, and observed a burst release of the
potential for the treatment of cancer and some other serious loaded drugs when the nanocarriers were exposed to NIR light,
diseases.248,253,254 The combination of photothermal therapy due to the photothermally induced phase transition of the
Figure 37. PEG and PEI dual functionalized nanographene oxide (NGO-PEG-PEI) for photothermally enhanced gene delivery. (a) A schematic
illustration of photothermally enhanced gene delivery. The mild photothermal heating could promote cellular uptake of nanocarriers. (b) Confocal
uorescence images of HeLa cells after transfection with plasmid encoding enhanced green uorescent protein (EGFP) by using NGO-PEG-PEI at
dierent N/P ratios for 20 min under various conditions: 37 C incubation, 43 C incubation, and 37 C incubation together with the 808 nm laser
irradiation (0.5 W/cm2). (c and d) Photothermally enhanced siRNA delivery. The expression levels of Plk1 mRNA (c) and protein (d) as
determined by qRT-PCR and Western blotting, respectively, in MDA-MB-435s cells after transfection with NGO-PEG-PEI/siRNA complexes at
dierent N/P ratios with or without laser irradiation (808 nm, 0.5 W/cm2, 20 min). Reprinted with permission from ref 291. Copyright 2013 John
Wiley & Sons, Inc.
coating polymer in which drug molecules are slightly increased from 37 to 43 C, the cell membrane
encapsulated274,275(Figure 35). Additionally, various mesopo- permeability would be signicantly enhanced, accelerating the
rous silica-coated NIR-absorbing nanostructures (e.g., Au NRs, cellular uptake of nanoparticles.256,289292 Utilizing this
Pd@Ag nanoparticle, CuS nanoparticles, graphene nanosheets) intriguing property, Sherlock et al. found that doxorubicin
or some NIR-absorbing nanostructures (e.g., AuAg NPs) (DOX) loaded ultrasmall FeCo/graphitic carbon shell (FeCo/
containing hydrogels have also been designed for drug delivery GC) nanocrystals with a high NIR light absorption exhibited a
and found to be promising for NIR light-controlled drug release fastened cellular uptake upon the laser irradiation.256,290 On the
due to the elevated temperature that promotes drug basis of the same mechanism, our group used functionalized
diusion276281 (Figure 36). In addition to these, several nano-GO for photothermally enhanced intracellular delivery of
groups have exploited DNA-coated NIR-absorbing nanostruc- photosensitizer (Ce6), DNA plasmid, and siRNA, aiming at
tures (e.g., AuNRs) for drug delivery and NIR-triggered release. combining photothermal therapy with photodynamic therapy
Upon the photothermally triggered melting of double-stranded as well as gene therapy123,291,293 (Figure 37). Distinct from the
(ds) DNA (or dsDNA-RNA hybrid) attached on nanocarriers above-mentioned strategy, Lapotkos group found that the
under NIR irradiation, the drug molecules stacked inside the plasmonic nanobublles (PNBs), generated from the NIR light
ds-DNA structure, or the complementary DNA or small irradiation of AuNPs adhered onto the plasma membrane,
interference RNA (siRNA) could be released, for various aimed could form transient pores on the plasma membrane, which
applications.282285 could contribute to a transient burst uptake of anticancer drugs
2.5.2. Photothermally Enhanced Drug Delivery. It has and plasmid DNA by the physical diusion, realizing a PNBs
been found that many nanoparticles, the majority of them with enhanced chemotherapy and gene delivery with a high
dierent sizes, shapes, and surface functionalization, are selectivity by conjugating the AuNPs with various cell specic
engulfed by cells mainly via energy-dependent pathways antibodies294297(Figure 38).
including clathrin-mediated and caveolae-mediated endocytosis, 2.5.3. Gold Nanomaterials for PTT-Based Cancer
macropinocytosis, and some others.286288 A number of studies Combination Therapy. In recent years, various Au
have uncovered that when the environmental temperature nanostructures with suitable surface modications have been
Figure 38. Plasmonic nanobubbles (PNB) enhance ecacy and selectivity of chemotherapy against drug-resistant cancer cells. (a) Principles of
plasmonic nanobubble therapies. (bd) Bright eld (I, III) and uorescent (II) microscopy images of a coculture of normal NOM9 cells and
squamous cell carcinoma HN31 cells (green in uorescent images or shown with arrows in bright eld images). The images in columns I and II were
taken before treatment, and those in column III were taken after the treatment. Dead cells were stained by Trypan Blue in I and III (blue-dead cells,
white-live cells). (b) PNB treatment with a single laser pulse (70 ps, 820 nm, 40 mJ cm2). (c) Nanohyperthermia treatment. (d) Cisplatin (5 g
mL1) treatment for 72 h. The PNB treatment appeared to be most eective and selective in terms of killing drug-resistant cancer cells without
harming normal cells. Reprinted with permission from ref 296. Copyright 2012 John Wiley & Sons, Inc.
extensively explored for the combined PTT and chemo- increased NIR light absorption were then observed, contribu-
therapy.298 AuNPs that can be easily prepared in a size- ting to an eective synergistic tumor suppression eect in
controllable manner have found various applications in the eld mouse xenografts.
of nanomedicine.31,299301 In 2012, Luo et al. fabricated AuNRs with strong NIR absorbance and suitable surface
aptamer/hairpin DNA conjugated AuNPs for drug delivery.283 modications have also been widely explored for the combined
It was found that the as-prepared drug carrier could selectively photothermal and chemotherapy of cancer.303306 One
deliver the loaded drug (DOX) into targeted cells and exhibited commonly used nanoplatform for photothermal responsive
a synergistic therapeutic eect by combining with laser drug release is mesoporous silica-coated AuNRs, which have
irradiation, showing a great potential for light controllable been widely studied for drug delivery and exhibit a high drug
drug delivery with limited side eects. In another recent loading capacity attributed to their mesoporous silica shells. In
work,302 You and co-workers prepared a drug carrier vehicle by 2012, Zhang et al. fabricated mesoporous silica-coated AuNRs
in suit reduction of potassium tetrachloroaurate (KAuCl4) in for DOX delivery, observing a precisely NIR light-controllable
the presence of sodium borohydride (NaBH4) in a pH drug release prole. It was demonstrated that the DOX-loaded
responsive matrix, obtaining nanoparticles homogeneously mesoporous silica AuNRs could oer a synergistic therapeutic
decorated with AuNPs. Such a nanostructure exhibited a high eect on A549 cancer cells by utilizing a 790 nm laser
absorption in the NIR region. After being conjugated with a irradiation.276 In another work, Qu group demonstrated that
targeting moiety (Herceptin) and loaded with anticancer drug mesoporous silica coated AuNRs capped with a dimeric G-
(DOX), the obtained drug carrier could be selectively engulfed quadruplex showed a great NIR light responsive drug release
by cancer cells, resulting in a combined therapeutic eect under prole and resulted in a targeted combined cancer cell killing
the NIR laser irradiation. Furthermore, Nam and colleagues eect in vitro282 (Figure 40). More recently, in another work by
designed a pH-responsive AuNP-based drug carrier, which the same group, they further showed that folic acid conjugated
could form aggregates in tumor regions by responding to the mesoporous silica-coated AuNRs with PEGylation after being
micro acidic environment of the tumors51(Figure 39). Highly loaded with an anticancer drug could realize a greatly enhanced
spatiotemporally concerted drug release and dramatically treatment eect by combining PTT with chemotherapy.307
Figure 39. pH-responsive assembly of Au nanoparticles for synergistic cancer therapy. The pH-responsive smart AuNP doxorubicin conjugate
(SANDC) inside the acidic tumor microenvironment would reduce DOX and get aggregated. While DOX could induce chemotherapy of tumors,
the aggregated AuNPs would show red-shifted absorbance and be able to generate heat under NIR laser irradiation. Such a mechanism allows for pH
responsive combined photothermal and chemotherapy with in vivo synergistic therapeutic eect. Reprinted with permission from ref 51. Copyright
2013 American Chemical Society.
Almost at the same time, a similar treatment eect in mice was drug loaded multifunctional nanoparticles could contribute to a
observed in the work by Shen and co-workers. In their study, synergistic tumor treatment eect in mouse xenografts.310
RGD peptide was introduced as the targeting moiety to realize Apart from AuNRs, AuNSs prepared via various methods
a targeted synergistic therapeutic eect in a mouse tumor with strong NIR light absorptions are also a useful nanoplat-
model308 (Figure 41). form for photothermal combination therapy.253,308,310 In 2008,
In addition to the use of mesoporous silica to coat AuNRs, Park and co-workers successfully prepared AuNSs on the
there have been a number of dierent AuNR-based NIR surface of PLGA nanoparticles. The obtained multifunctional
responsive drug delivery systems by coating AuNRs with other nanoparticles were explored for the loading of anticancer drug
thermal-responsive materials such as DNA or polymers. Kim et (DOX) and found to be eective in killing cancer cells by
al. demonstrated that aptamer conjugated AuNRs with a DNA combining PTT with chemotherapy, showing a great potential
linker (40 base pairs) could be used for targeted anticancer to limit the side eect of treatment by localizing the treatment
drug (DOX) delivery, showing a powerful synergistic tumor to tumorigenic regions.262,263 In 2009, a similar AuNS system
regression eect both in vitro and in vivo under the irradiation after being conjugated with a targeting moiety (Cetuximab)
showed an excellent targeted delivery ability and was found to
of a NIR laser.309 Besides, after being coated with a mesoporous
be eective in killing cancer cells by combining PTT with
silica shell, AuNRs were found to be outstanding for drug
chemotherapy.311 In 2010, Lee and co-workers fabricated an
delivery with a precisely NIR light-controllable release
interesting half-AuNS nanostructure on the template of PLGA
prole.304 Besides, our group designed a smart drug carrier nanoparticles, and used such a nanoplatform for drug delivery,
by modifying AuNRs with thermosensitive block copolymers achieving eective tumor regression under the NIR light
lipoylated poly(ethylene glycol)-b-poly(-caprolactone) (PEG- irradiation after both i.t. and iv injection.312 In 2011, Liu and
PCL-LA). The obtained polymer-coated AuNRs after loading co-workers indicated that multifunctional AuNSs growth on the
with DOX exhibited an excellent NIR light responsive drug silica nanorattles after being loaded with the anticancer drug
release property and could oer a synergistic cancer treatment (docetaxel) could contribute to eective tumor inhibition when
eect on both wide-type and drug resistance MCF-7 cells275 combinedly used with the photothermal treatment, showing a
(Figure 42). In addition to those, Cheng et al. demonstrated signicantly decreased systemic toxicity as compared to its
that a novel type of multifunctional polymeric nanoparticles commonly used counterpart (Taxotere) in clinic.313 In a
obtained by decorating the poly(lactic-co-glycolic acid) (PLGA) following work by the same group, the authors conjugated the
nanoparticles with AuNRs could be exploited for the loading as prepared AuNSs with a targeting moiety (Transferrin, Tf).
and delivery of hydrophobic anticancer drugs. The obtained The obtained Tf conjugated AuNSs after drug loading exhibited
Figure 40. Aptamer gated AuNR nanovehicles for NIR triggered, targeted drug delivery to cancer cells. (a) Scheme of illustration for NIR light-
triggered release of guest molecules from aptamer-covered AuNR nanovehicles. Drug molecules stacked inside double-strand DNA (dsDNA) coated
on AuNRs could be released upon NIR light induced photothermal heating of AuNRs that induces the denaturing of dsDNA. (b) Release proles of
a model drug molecule from nanovehicles (1 mg/mL) triggered by 808 nm NIR light at power density of 1.2 W/cm2 (black, a) and 0.6 W/cm2
(gray, b) for 10 min. (c) Fluorescence microscopy images of MCF-7 cell incubated with nanovehicles in dark (1) or with 808 nm laser irradiation
(2). Bright colored cells are live cells. Reprinted with permission from ref 282. Copyright 2012 John Wiley & Sons, Inc.
an improved therapeutic eect both in vitro and in vivo in could be dramatically increased by irradiating the cells with an
comparison with those without Tf conjugation314 (Figure 43). 808 nm laser at a low power density to induce a mild
Additionally, hollow AuNSs (HAuNSs) synthesized by photothermal heating (up to 43 C in the cell culture),
sacricial galvanic replacement of cobalt nanoparticles in the realizing a photothermally enhanced photodynamic killing of
presence of chloroauric acid have a strong absorption in NIR cancer cells.123 After that, in another piece of work by our
region and have been intensively explored for drug delivery and group, it was found that the gene transfection eciency of a
photothermal ablation of tumors by Li group and nano-GO-based gene delivery carrier could also be greatly
others.258,261,315317 In 2012, Li and co-workers demonstrated improved by a mechanism similar to that aforementioned,
that HAuNSs could be used for in vivo anticancer drug delivery showing a potent potential for combined PTT and gene
and exhibited eective synergistic tumor suppression ability therapy.291 Regarding in vivo combined therapy, in 2012,
when combined with the NIR light irradiation. Further Zhang and co-workers demonstrated that PEGylated nano-GO
explorations indicated that AuNSs, after being conjugated after loading with DOX could be used for in vivo combined
with a peptide targeting EphB4 overexpressed on the
chemotherapy and PTT, showing an eective tumor inhibition
membrane of multiple types of cancer cells, exhibited an
eect in a mouse xenograft tumor modal.164 More recently,
improved cellular uptake for three EphB4 positive tumors both
another work by Yang and co-workers demonstrated that
in vitro and in vivo. The improved tumor accumulation of
peptide conjugated AuNSs and NIR trigged release of DOX PEGylated nano-GO after conjugation with Cetuximab (C225),
ultimately contributed to an eective synergistic therapeutic which targeted the epidermal growth factor receptor (EGFR),
eect on EphB4 positive tumors.318320 could be exploited for tumor-targeted anticancer drug
2.5.4. Other Inorganic Nanomaterials for PTT-Based (epirubicin, EPI) delivery, realizing triple-therapeutics (growth
Cancer Combination Therapy. In addition to Au nanoma- signal blocking, chemotherapy, PTT) to inhibit tumor growth
terials, many other NIR absorbing inorganic nanomaterials have in mice321 (Figure 44). Besides directly using nano-GO for
also been proven to be promising for potential combined PTT drug delivery, Wang et al. successfully grew a mesoporous silica
and chemotherapy.298 Apart from being used for the photo- shell around the GO sheet and utilized the obtained
thermal treatment of tumors, nano-GO has been found to be nanocomposite for DOX loading. After conjugation with a
promising for the combination therapy of cancers by exploiting targeting peptide, targeted delivery of DOX and combined
its excellent photothermal conversion ability. In 2011, we found photothermal and chemotherapy were then demonstrated with
the cellular uptake of PEGylated nano-GO loaded with Ce6 glioblastoma cancer cells.277
Figure 41. Targeting mesoporous silica-encapsulated AuNRs (AuNRs@mSiO2) for chemo-photothermal therapy with NIR irradiation. (a and b)
Representative TEM image of AuNRs (a) and AuNRs@mSiO2 (b). (c) UVvisNIR extinction spectra of AuNRs and AuNRs@mSiO2. (d and e)
IR thermal images of a tumor-bearing mouse taken before (e) and 30 s after (f) 808 nm NIR laser irradiation at 3 W/cm2. This mouse was iv injected
with AuNRs@mSiO2-RGD before laser irradiation. (f) Photograph of tumors after excision from (1) untreated group, (2) laser group, (3) DOX
group, (4) AuNRs@mSiO2-RGD with laser group, and (5) DOX-AuNRs@mSiO2-RGD with laser group. Reprinted with permission from ref 308.
Copyright 2013 Elsevier.
Because of their excellent photothermal conversion ability, showed an eective tumor growth inhibition eect in mice
various CuS nanostructures have also explored for combined under irradiation with a 980 nm laser323 (Figure 45).
PTT and chemotherapy of tumors. Recently, Zha et al. Pd nanosheets, another type of NIR light absorbing inorganic
demonstrated that gelatin-modied CuS nanoparticles could be nanostructures, have also been explored for the photothermal
exploited for DOX loading, realizing an eective combination ablation of tumors as well as combined cancer therapy.196,197,279
treatment of cancer cells in vitro under the NIR light In 2012, Zhengs group synthesized a mesoporous silica-coated
irradiation.322 Dong and co-workers synthesized hollow CuS
Pd@Ag nanoplate composite with great photothermal stability.
nanoparticles and utilized them for anticancer drug loading and
delivery, resulting in a synergistic treatment of tumors in mouse It was demonstrated that as-prepared mesoporous shell with an
xenografts under the irradiation of a 980 nm NIR laser.280 In average pore size of 10 nm exhibited an improved drug
another work by Song and co-workers, the authors prepared loading capacity. The loaded drug could be trigged to release in
mesoporous silica-coated Cu9S5 multifunctional coreshell response to the external pH decrease and the photothermal
nanoparticles, which after being loaded with DOX again eect due to NIR light irradiation. The obtained drug loaded
Figure 42. AuNR-cored micelles (AuNR-M) as a robust and remotely controllable doxorubicin release system for potent inhibition of drug-resistant
cancer cells. (a) Scheme of AuNR-cored biodegradable micelles based on lipoylated poly(ethylene glycol)-b-poly(-caprolactone) (PEG-PCL-LA)
block copolymer for NIR-triggered release of DOX in cancer cells. (b) NIR-induced reversal of drug-resistance with AuNR-M-DOX. (c)
Dependence of cell viabilities on DOX concentrations for MCF-7/DOXR cells treated with free DOX, AuNR-M-DOX, and AuNR-M-DOX with
NIR irradiation. Reprinted with permission from ref 275. Copyright 2013 American Chemical Society.
nanocomposites again were proven to be eective for in vitro for loading of various aromatic drug molecules, including two
combined chemotherapy and PTT.279 chemotherapy drugs DOX and SN38, and a photodynamic
2.5.5. Organic NIR-Absorbing Nanoagents for PTT- agent Ce6, with high loading eciencies.324 In vitro studies
Based Cancer Combination Therapy. Similar to the use of revealed a signicant synergistic anticancer therapeutic eect
inorganic photothermal nanoagents for combined photo- when chemotherapy is combined with photothermal treatment
thermal and chemotherapy, small NIR light absorbing using those PEGylated PEDOT:PSS nanoparticles as a NIR-
molecules (e.g., ICG, IR825) and several organic polymers responsive nanocarrier.
(e.g., PEDOT:PSS, PPy) have been found to be eective for the In another recent work by our group, we prepared a novel
photothermally enhanced chemotherapy in vitro and in type of multifunctional nanoparticles by coating Fe3O 4
vivo.324326 Recently, Zheng and co-workers fabricated DOX nanoclusters with PPy polymer, obtaining Fe3O4@PPy core
and ICG coloaded PLGA-lecithin-PEG nanoparticles (DINPs) shell nanoparticles, which were further coated with PEG. The
using a single-step sonication method (Figure 46). Remarkably, obtained Fe3O4@PPy-PEG nanoparticles showed high NIR
those DINPs oered a synergistic antitumor eect and showed light absorption and strong magnetic property, and could serve
eective tumor suppression in both DOX-sensitive MCF-7 and as an eective drug-loading platform for the delivery of
DOX-resistance MCF-7/ADR xenografts after only one dosage anticancer drugs such as DOX. While an external magnetic eld
with laser irradiation.326 could locally enhance the cellular uptake of those nanoparticles,
NIR-absorbing conjugated polymers with delocalized - NIR light with a relatively low power density could not only
electrons have been demonstrated to be a new class of light- promote cellular entry of those Fe3O4@PPy-PEG-DOX
responsive drug delivery platforms to load various types of nanoparticles, but also trigger the DOX release inside cells
aromatic therapeutic molecules via stacking and hydro- (Figure 47). All of those would result in remarkably enhanced
phobic interactions. A latest work by our group demonstrated cancer cell killing under both magnetic and NIR light external
that PEDOT:PSS nanoparticles with PEGylation could be used controls. In vivo imaging-guided combination therapy was
Figure 43. Targeting Au nanoshells on silica nanorattles (GSNs) for combined therapy. (a) Schematic diagram of GSNs synthesis and
bioconjugation. (b) A TEM image of silica nanorattles. (c) A TEM image of GSNs. (d) Extinction spectra of GSNs and PEGylated GNSs conjugated
with transferrin (pGSNs-Tf). (e) In vivo antitumor activities of control group, pGSNs-NIR, Texotere (Doc), pGSNs-Doc-NIR, pGSNs-Doc-Tf-NIR
group on MCF-7 bearing nude BALB/c mice. (f) Photographs at day 17 of representative mice from groups of (f1) control, (f2) pGSNs-NIR, (f3)
Texotere, (f4) pGSNs-Doc-NIR, and (f5) pGSNs-Doc-Tf-NIR. Reprinted with permission from ref 314. Copyright 2012 John Wiley & Sons, Inc.
further realized using those multifunctional nanoparticles, 3.1. Organic Nanoparticles as Nanocarriers of
showing excellent synergistic antitumor eect in vivo when Photosensitizers for Photodynamic Therapy
chemotherapy was combined with PTT.325 Biodegradable organic-based nanoparticles have been exten-
sively used in drug delivery applications, including the delivery
3. PHOTODYNAMIC THERAPY BASED ON of photosensitizers for photodynamic cancer treatment.
NANOMATERIALS However, because this is a relatively mature eld, which has
Photodynamic therapy (PDT) involves the administration of been systematically summarized in a number of previous review
photosensitizing (PS) agents, and then irradiation with light at articles,334,337342 we will only briey introduce several major
appropriate wavelengths to induce cell death. The overall classes of organic nanocarriers for the delivery of PDT without
reaction generates reactive oxygen species (ROS), such as getting into details.
singlet oxygen (1O2) and free radicals, which are toxic and Liposomes are articially prepared vesicles composed of lipid
would be able to kill cancer cells. In cancer treatment, PDT has bilayers. Liposomes are likely the most popular nanocarrier
emerged as an important method in preclinical research and system in the area of drug delivery. Regarding the delivery of PS
clinical practice because it is a less invasive technique, and the molecules for PDT, liposomes have also been extensively used
resulting photodynamic eect can be limited to the area of due to their high loading capacity and exibility for
interest, leaving the surrounding healthy tissues and cells modication.343,344 For instance, the photofrin encapsulated
undamaged.327331 However, many currently developed PS liposomes exhibited signicantly higher photodynamic ecacy
molecules are hydrophobic and tend to aggregate easily in against a human glioma implanted in rat brain as compared to
aqueous media, leading to a decrease in its quantum yield and photofrin only.16 As a commercial product of liposomal PDT
problems for intravenous administration.332 Other factors such agent, Visudyne containing verteporn, abenzoporphyrin
as poor selectivity in terms of target tissue and healthy tissue, derivative, has been approved for the treatment of age-related
low extinction coecients, and absorption at relatively short macular degeneration (AMD), which is caused by abnormal
wavelengths have also limited the eciency of PDT in clinical choroidal neovascularization.345
cancer treatment. The use of nanoparticle carriers of the Micelles are spherical supermolecular complexes formed
delivery of photosensitizers has thus been widely explored, spontaneously when amphiphilic molecules or copolymers are
aiming at solving all or some of the above-mentioned problems dissolved in an aqueous environment above the critical micelle
in traditional PDT using free PS agents333336(Table 1). concentration (CMC). Polymeric micelles have been used to
Figure 44. EGRF conjugated PEGylated nanographene oxide (NGO) for targeted chemotherapy and photothermal therapy. (a) Scheme of the
procedure for preparation of PEG-NGO-C225/EPI. (b) The mechanism of nanocarriers captured and anchored to the cell surface through an
antibodyreceptor interaction for targeted chemo-photothermal therapy and inhibition of EGFR signal. (c) Quantitative analysis of the eects of
various treatments on tumor sizes. Representative uorescence images of tumors from control and treatment mice (inset). (d) Photographs of
representative mice before treatment (left) and 21 days after treatment (right). Reprinted with permission from ref 321. Copyright 2013 Elsevier.
carry hydrophobic photosensitizers, which are physically the nonformulated drug. TPP-loaded PEG-PE micelles were
entrapped in and/or covalently bound to the hydrophobic additionally modied with tumor-specic monoclonal 2C5
cores. Polymers used for photosensitizer encapsulation include antibody (mAb2C5), which resulted in signicantly improved
poly(ethylene glycol)-poly(-caprolactone)(PEG-PCL), plur- anticancer eect of the drug under the PDT conditions against
onics, PEGylated lipids, and many other types.342,346350 Li murine Lewis lung carcinoma in vivo.
et al. used PEG-PCL copolymer to encapsulate a PS molecule, Natural degradable polymers including polysaccharides and
protoporphyrin IX (PPIX), forming PPIX-loaded PEG-PCL proteins have been also used in the delivery of PDT.356,357
micelles, which showed improved PDT eciency as compared Commonly used natural biodegradable polymers include
to free PPIX.351 PEG-PCL micelles have also been used for the alginate, chitosan, dextran, albumin, ferritin, gelatin, collagen,
encapsulation of other PS molecules such as phthalocyanines, agars, and others. For example, Yoon et al. used hyaluronic acid
chlorins, and pheophorbides with many successful re- nanoparticles (HANPs) containing Ce6 for simultaneous
sults.352354 PEG-lipid micelles are another class of extensively imaging and PDT.358 Self-assembled HANPs were synthesized
studied micelles for PDT delivery. For example, Torchilin et al. by chemical conjugation of aminated 5-cholanic acid, PEG,
studied poly(ethylene glycol)-phosphatidyl ethanolamine and black hole quencher3 (BHQ3) to the HA polymers. Ce6
(PEG-PE) micelles as PS delivery systems.355 The use of was readily loaded into HANPs by a simple dialysis method,
PEG-PE micelles allowed for a 150-fold increase in the resulting in Ce6-loaded hyaluronic acid nanoparticles (Ce6-
solubilization of tetraphenylporphyrin (TPP), as compared to HANPs). After iv injection into the tumor-bearing mice, Ce6-
Figure 45. Cu9S5@mSiO2 coreshell nanocomposites for combined photothermal and chemotherapy. (a) Schematic illustration showing the use of
Cu9S5@mSiO2PEG coreshell nanocomposites as a multifunctional nanoplatform for combined photothermal- and chemotherapy. (b) IR thermal
imaging of two mice injected with Cu9S5@mSiO2PEG coreshell nanocomposites (left mouse, 0.15 mL, 450 g/mL) or saline (right mouse, the
control) via the hypodermic injection. (c and d) In vitro combination therapy. The cell viability data (c) and inhibition rate (d) of Hep3B cells
incubated with free DOX, Cu9S5@mSiO2PEG, and DOX-loaded Cu9S5@mSiO2PEG as a function of the nanoparticle concentration. (e)
Photograph of tumors from the control group, DOX group, Cu9S5@mSiO2+NIR group and Cu9S5@mSiO2DOX + NIR group collected 10 days
after the treatment was initiated. (f) Representative photographs of the mice from dierent groups on the tenth day. Reprinted with permission from
ref 323. Copyright 2013 John Wiley & Sons, Inc.
HANPs could eciently reach the tumor tissue via the passive Dendrimers are highly branched macromolecules composed
targeting mechanism and specically enter tumor cells through of repetitive units branched on a multivalent core molecule.
the receptor-mediated endocytosis based on the interactions Photosensitizers can be attached at the periphery of the
between HA on nanoparticles and CD44, the HA receptor on dendrimer branches or have been capsulated in the core of a
the surface of tumor cells. Upon laser irradiation, Ce6 that was dendrimer. For instance, Nishiyama et al. developed a novel
released from nanoparticles could generate uorescence and class of photosensitizer formulation,360 the dendrimerphthalo-
singlet oxygen inside tumor cells, resulting in eective cyanine (DPc)-encapsulated polymeric micelle (DPc/m). In
suppression of tumor growth. Recently, Zhen et al. used animal experiments, the authors found that DPc/m showed
protein-based nanoplatforms for photosensitizer delivery359- signicantly higher antitumor activity than clinically used PHE.
(Figure 48). They demonstrated that the RGD-modied Therefore, DPc/m is expected to serve as an innovative
ferritin (RFRT) nanoparticles were safe and ecient carriers photosensitizer formulation to improve the eectiveness and
for zinc-hexadecauorophthalocyanine (ZnF16Pc) with an safety of current PDT.
extremely high loading rate and an ultrasmall particle size. In Hollow polymer microcapsules or vesicles can also be used to
their animal experiment, they found that ZnF16Pc-loaded- encapsulate a wide variety of therapeutic agents included PS
RFRTs showed a high U87MG tumor accumulation (tumor-to- molecules for PDT. In general, those capsules are prepared by
normal tissue ratio of 26.82 4.07 at 24 h) and a good tumor the sequential deposition of oppositely charged polyelectrolytes
inhibition rate (83.64% on day 12) after PDT, and thus hold onto charged templates using the so-called LBL method.
great potential in clinical translation. Bedard et al. demonstrated a laser-induced remote opening of
Figure 46. Doxorubicin/indocyanine green (DOX/ICG) coloaded lipid-polymer nanoparticles (DINPs) for highly eective chemo-photothermal
combination therapy. (a) Schematic illustration of the single-step sonication to synthesize DINPs. Photograph of mixture containing DOX, ICG,
lecithin, and DSPE-PEG before (left) and after (right) sonication. (be) In vivo chemo-photothermal therapy of DINPs. (b) Wide-type MCF-7
tumor growth curves of dierent groups after treatments. (c) Survival rates of mice bearing wide-type MCF-7 tumors after treatments. (d) Drug
resistant MCF-7/ADR tumor growth curves of dierent groups after treatments. (e) Survival rates of mice bearing MCF-7/ADR tumors after
treatments. Reprinted with permission from ref 326. Copyright 2013 American Chemical Society.
polyelectrolyte capsule.361 The porphyrin PS molecule, tetrakis nanospheres,362 which showed higher 1O2 generation eciency
(4-sulfonatophenyl) porphyrin (TPPS), was introduced into and enhanced in vitro phototoxicity than monomeric Pc
the PE capsule wall as the light absorbing species. They found molecules. Overall, nanocapsules if well-designed could serve as
that under laser irradiation, the photodynamic property of an interesting platform to develop PDT nanoagents usually
TPPS would lead to light-induced destabilization of the with multiple functions.
polyelectrolyte multilayers, resulting in deformation of the 3.2. Inorganic Nanoparticles as Nanocarriers of
capsules. Such a system has the potential to be developed into a Photosensitizers for Photodynamic Therapy
remotely controlled drug-releasing platform. In another work,
Son et al. reported the preparation of hollow nanocapsules by Besides organic nanoparticles used in the delivery of photo-
the LBL technique17(Figure 49). Adendrimerporphyrin (DP) dynamic agents, various inorganic nanomaterials with interest-
was introduced not only as the PS molecule but also to oer ing structures as well as unique physical and chemical
negative charges, the latter of which could be utilized in the properties have also been explored to construct photodynamic
deposition of counter-charged polymers by LBL. After removal nanoagents.
of the template core, stable hollow nanocapsules were 3.2.1. Silica Nanoparticles. Silica as a major component of
successfully obtained and used for combined PDT and sand is known for its compatibility in biological systems. A large
chemotherapy. Very recently, Hota et al. demonstrated the variety of silica-based nanostructures have been synthesized in
design and one-pot direct synthesis of covalently linked ZnPc the past few decades for dierent aimed applications.363 The
Figure 47. Iron oxide @ polypyrrole (Fe3O4@PPy) nanoparticles as a multifunctional drug carrier for remotely controlled cancer therapy. (a)
Schematic illustration to show the synthesis of Fe3O4@PPy-PEG nanoparticles, the subsequent drug loading, and the remotely controlled cancer cell
killing under dual physical stimuli. (b) Schematic illustration of in vitro combination therapy. (c) Relative viabilities of 4T1 cells after incubation with
DOX, Fe3O4@PPy-PEG, and Fe3O4@PPy-DOX-PEG in the presence and absence of a magnetic eld (30 min), with or without laser irradiation
(808 nm, 350 mW/cm2, 10 min). (d,e) In vivo combination cancer therapy. (d) Tumor growth curves of dierent groups of mice after various
treatments indicated. (e) Body weights of mice after various treatments indicated. Reprinted with permission from ref 325. Copyright 2013 American
Chemical Society.
particle size, shape, porosity, and surface chemistry can be easily collaborators reported the covalent incorporation of PS
controlled during the preparation of silica nanostructures. molecules into ORMOSIL nanoparticles.368 In this study, to
Silica-based nanoparticles have also been successfully used to avoid any drug release during systemic circulation, PS
encapsulate various photosensitizers for PDT applica- molecules were covalently linked to ORMOSIL. These
tions.363365 nanoparticles could be avidly taken up by tumor cells in
In as early as 2003, Kopelman et al. showed that mesometa- culture and showed strong phototoxicity upon irradiation with
tetra (hydroxyphenyl) chlorine (m-THPC), a commonly used light, demonstrating the potential of those nanoparticles for
PS molecule, could be encapsulated into silica nanoparticles.366 PDT.
In 2005, the same group published the encapsulation of Other types of silica particles have been used for the
methylene blue into organically modied silicates (ORMOSIL) encapsulation of PS for PDT. Wei and collaborators have
nanoparticles for the delivery of PDT.367 Prasad and elaborated porous hollow silica nanospheres embedded
Figure 48. Ferritin nanocages to encapsulate and deliver photosensitizers for ecient photodynamic therapy. (a) Schematic illustration of the
formation and working mechanism of F-ZnPc loaded RGD-modied ferritin (P-RFRTs). (b) Photographs of P-RFRTs and free ZnF16Pc in PBS
under dierent conditions. (c) In vivo and ex vivo uorescence imaging results. In vivo uorescent images were taken 24 h after iv injection with P-
RFRTs. For ex vivo images taken at 24 h post injection, the organs were arranged in the following order: (1) tumor; (2) heart; (3) liver; (4) spleen;
(5) skin; (6) lung; (7) kidneys; (8) intestine; (9) muscle; (10) brain. (d) Immunouorescence microscopic images. Integrin v3 was upregulated
on both tumor vasculature and tumor cells. Scale bars: 50 m. (e and f) Tumor growth curves (e) and body weight curves (f) in dierent groups
after treatment. (g) Caspase 3 staining of tumor sections. (h) H&E staining with tumor tissues. Scale bars: 10 m. Reprinted with permission from
ref 359. Copyright 2013 American Chemical Society.
hypocrellin A (HA).369 As compared to free HA, the silica encapsulated inside MSNs with a hydrodynamic diameter of
embedded HA showed superior light stability and higher 1O2 118 nm. This study demonstrated that a single injection was
generation. The same group later reported the preparation of sucient to induce a major reduction of the tumor size upon
HA nanoparticles by reprecipitation to form 110 nm silica two-photon irradiation with NIR light. Tu et al. conjugated a
nanovehicles.370 The resulting embedded HA also showed photosensitizer, protoporphyrin IX, with MSNs through
superior light-stability, higher 1O2 generation ability, and better covalent bonding to yield PpIX-modied MSNs (PpIX-
PDT cancer cell killing ecacy than free HA. MSNs) for PDT study373(Figure 50). In vitro experiments
Mesoporous silica nanoparticles (MSNs) with high pore with HeLa cells showed the high cellular-uptake eciency of
volume, large surface area, as well as uniform pore size have PpIX-MSNs, whose phototoxicity was found to be both
shown great promise as drug delivery vehicles.371 Gary-Bobo et irradiation time- and dosage-dependent.
al. used mannose-functionalized MSNs for tumor-targeted Overall, silica-based nanoparticles for applications in PDT
ecient two-photon PDT.372 Photosensitizer PS was covalently have emerged as a promising eld for the treatment of cancer as
Figure 49. Photosensitizing hollow nanocapsules for combination cancer therapy. (a) Procedure for the preparation of multilayer hollow
nanocapsules starting from dendrimer porphyrin (DP). (b) SEM and TEM images of NCs before and after removal of PS nanoparticles. NC1, NC2,
and NC3 contain 1, 2, and 3 layers of DP molecules, respectively. (c) SEM images of hollow nanocapsules (NC3) that were treated with solutions of
dierent pH values for 1 day. Scale bars are 500 nm except for right-hand TEM images (100 nm). (d) Amount of DOX loading in hollow NCs and
NCs@PS. (e) Amount of DOX released from cross-linked and non-cross-linked NCs. (f) Relationship between reaction time of EDC/NHS cross-
linking on the percentage of free amine content of multilayer shells in NCs. (g) Comparison of cell viability following chemotherapy (NCs@DOX),
PDT (NCs with light), and combined therapy (NCs@DOX with light). Reprinted with permission from ref 17. Copyright 2011 John Wiley & Sons,
Inc.
it appears to be a safe drug delivery system. Multiple physiologic conditions, PEG was conjugated to the surface of
functionalities could be integrated into well-designed silica- AuNPs, forming PEGylated AuNPs. In a recent work, Cheng et
based nanoplatforms, which are useful in photodynamic cancer al. found that PEGylated AuNPs were highly ecient drug
treatment as well as cancer theranostics. vectors for PDT. With the AuNP-phthalocyanine 4 (Pc4)
3.2.2. Metallic Nanoparticles. Metallic nanoparticles, such conjugates, the drug delivery time required for PDT has been
as Au, Ag, and Pt NPs, possess many fascinating properties, and greatly reduced to less than 2 h, as compared to 2 days for the
have been widely explored for applications in biomedicine. free drug.377 In another work, Obaid et al. also reported the
Among all of the metallic nanoparticles, AuNPs are well-known synthesis and applications of AuNPs functionalized with Zn-Pc
for their chemical inertness and minimum acute cytotoxicity. photosensitizer and thiol-functionalized PEG,378 and demon-
Unlike silica-based nanoparticles, the conjugation/loading of PS strated targeted PDT killing of HT-29 human carcinoma cells
molecules to AuNPs and other inorganic nanoparticles usually (Figure 51).
happens on the surface of the metallic nanoparticles. Because The localized surface plasmon resonance of Au can be used
metallic nanoparticles can be conned to an extremely small for plasmonic imaging and improved hyperthermal/photo-
size, a large dose of photosensitizer can be loaded due to the dynamic treatment. Wang and collaborators showed in an in
enormous surface area. It is possible to modify the AuNPs vitro study that electrostatically conjugated 5-aminolevulinic
either covalently or noncovalently with PS molecules.374,375 acid (5-ALA) AuNPs could signicantly enhance the PDT
In 2002, Hone et al. synthesized small AuNPs (24 nm eciency toward cancer cells.379 It was reported that PpIX,
diameter) stabilized with a zinc(II) Pc (Zn-Pc) derivative, which was converted from 5-ALA in malignant gliomas through
whose mercaptoundecyl group could be attached to the surface metabolic conversion in the mitochondria, accumulated
of AuNPs through the formation of stable SAu bonds.376 preferentially in brosarcoma tumor cells treated with 5-ALA-
Those Zn-Pc-loaded AuNPs were able to generate 1O2 upon conjugated AuNPs, yielding signicantly higher ROS gener-
light irradiation with the enhanced quantum yield as compared ation and 50% greater cytotoxicity than that with free 5-ALA
to that of free molecules. To inhibit colloid aggregation in under light exposure. In 2012, the same group studied the size-
Figure 50. Mannose-functionalized mesoporous silica nanoparticles for ecient two-photon photodynamic therapy of solid tumors. (a and b)
Synthesis of MSN1-mannose nanoparticles. (c and d) Renal clearance and biocompatibility of MSN1-mannose. (c) Photodynamic therapeutic eect
on tumor groups. (d) Renal clearance of nanoparticles evaluated over a period of 2 weeks after iv injection at a dose of 16 mg/kg. Reprinted with
permission from ref 373. Copyright 2011 John Wiley & Sons, Inc.
dependent enhancement of ROS formation enabled by Au NPs they found that that {100} facet-enclosed Pd nanocubes
with dierent diameters as 19, 66, and 106 nm.380 They exhibited superior catalytic performance to {111} octahedrons
observed the ROS generation was enhanced with the increase in glucose oxidation. In the same way, Pd (100) could provide
of AuNP sizes. AuNP-enhanced and size-dependent ROS better capability to kill HeLa cells than Pd(111). The intrinsic
formation could be attributed to the localized electromagnetic PDT eect of those metallic nanoparticles merits further in-
eld as a result of surface plasmonic resonance of AuNPs under depth investigations.
light irradiation. 3.2.3. Magnetic Nanoparticles. Magnetic nanoparticles
Interestingly, single oxygen can be also generated from the (MNPs), such as iron oxide nanoparticles (IONPs), are of great
metal nanoparticles without photosensitizers. In 2011, interest to researchers due to their intrinsic diagnostic
Vankayala et al. reported an unprecedented observation that capabilities in MR imaging, magnetic hyperthermia properties,
singlet oxygen could be formed through direct sensitization by and the ability to target the drug delivery via magnetic
metal nanoparticles (Ag, Pt, and Au) without the presence of attraction, oering great potential for clinical diagnostics and
any organic photosensitizers.381 Direct evidence includes the therapeutics.1820 One of the very few types of FDA approved
observation of phosphorescence emission of 1O2 at approx- inorganic-based nanomaterials for in vivo use is polymer-coated
imately 1268 nm, hydroperoxidation of olens, uorescence of superparamagnetic IONPs agents for MR imaging. In past
a selective 1O2 sensor, and the quenching of 1O2 phosphor- years, many dierent groups have explored the use of MNPs in
escence by sodium azide. However, those nanoparticles were the delivery of PDT and MR imaging guided PDT.
not tested in vitro. In a very recent work, Xiong and PS molecules could be conjugated to MNPs for simultaneous
collaborators demonstrated that surface facet is a key parameter MR imaging and PDT. As a typical example, Reddy et al. in
to modulate the O2 activation process on metal nanocrystals.382 2006 developed F3 peptide-targeted polymeric nanoparticles
By employing single-facet Pd nanocrystals as a model system, consisting of encapsulated imaging agent (iron oxide) and
Figure 51. Au nanoparticles for the delivery of photodynamic cancer therapy. (a) Schematic of the Pc (blue) and PEG (black) cofunctionalized
AuNPs conjugated with T antigen-specic lectin, jacalin (green). (b and c) MTT viability assay of HT-29 cells incubated for 3 h with varying
concentrations of nonconjugated (b) and jacalin-conjugated (c) nanoparticles, with (orange) and without (dark cyan) light irradiation. (d)
Photodynamic toxicity of jacalin-conjugated (red X) and nonconjugated (blue X) nanoparticles after PDT treatment of HT-29 cells. (e) Inhibition of
photodynamic toxicity of jacalin-conjugated nanoparticles by Asialofetuin or Me--Gal to block jacalin. Reprinted with permission from ref 378.
Copyright 2012 John Wiley & Sons, Inc.
photosensitizer (Photofrin) for targeted brain tumor therapy complexes could be utilized for the phosphorescence imaging
and the monitoring of therapeutic responses383 (Figure 52). and simultaneous 1O2 generation to induce cancer cell
Animals treated with F3-targeted nanoparticles were found to apoptosis. Wu and collaborators designed multifunctional
have the largest increase in diusion values and the longest Fe3O4TiO2 nanocomposites for MR imaging and PDT.385
survival time over the other treatment groups, demonstrating In this system, the Fe3O4 core was used to produce T2-
the versatility and ecacy of the brain tumor-targeted weighted MR contrast, and the TiO2 shell could serve as an
multifunctional nanoparticle system. inorganic photosensitizer for PDT. MCF-7 cells incubated with
Besides attaching organic PS molecules to MNPs for PDT, those Fe3O4TiO2 nanocomposites could be killed under the
inorganic ions or nanostructures that could intrinsically irradiation of UV light.
produce ROS under light irradiation could also be coupled In addition to the use of MNPs in MR imaging-guided PDT,
with MNPs for theranostic applications. Lai et al. designed a those nanoparticles could also be utilized to enhance tumor
three-in-one coreshell type of nanoparticles that was homing of PS molecules under magnetic targeting. In 2011, Cui
composed of Fe3O4 core and SiO2 shell with Ir(III) complex and collaborators demonstrated simultaneous magnetic eld
encapsulated.384 While the Fe3O4 core was useful in MR (MF) targeted PDT and in vivo dual-mode NIR uorescence
imaging, the SiO2 shell containing phosphorescent Ir(III) imaging and MR imaging using Ce6 loaded MNP-nano-
injection of IONC-PEG-Ce6 and 704 nm NIR light exposure at

an optical dose of 27 J/cm2. Therefore, the IONC-PEG-Ce6
presented in this work may be a useful multifunctional agent
promising in NIR-induced photodynamic cancer treatment
under magnetic targeting.
3.2.4. Semiconducting QDs. Quantum dots (QDs) are
semiconductor nanocrystals with high quantum yields, great
photostability, tunable uorescent emission properties, rela-
tively broad excitation wavelengths, and sharp emission
peaks.388392 It has been found that QDs can produce 1O2
under direct photoactivation. In 2003, Samia et al. employed
hydrophobic-capped CdSe QDs dissolved in oxygen saturated
toluene and observed noticeable 1O2 production under light
irradiation with an eciency at 5%.21 They found that this low
quantum eciency for 1O2 production by QDs was due to
ultrafast carrier trapping, nonradiative carrier relaxation, and the
large hydrodynamic size of QDs, while conventional PS
molecules based on porphyrins with small hydrodynamic size
and long-living triplet state could produce 1O2 at much higher
eciencies (>75%).
Despite the disadvantage of low eciency in using QDs for
PDT as compared to conventional PS molecules, QDs show
exceptional photostability, which oers cumulative eects in
PDT. For example, Anas et al. found that prolonged
photoactivation of a QD-plasmid DNA conjugate at 512 nm
resulted in the breakage and damage of DNA393 due to the
photosensitized production of ROS. Their results suggest that
QDs are promising PS drugs for nucleus targeted PDT if
combined with intranuclear delivery of QDs in cancer cells. In
another work, Chen et al. reported that CdSe QDs could
eectively eliminate nasopharyngeal carcinoma cells under light
exposure.394 They demonstrated that TGA-coated QDs, when
partially oxidized, functioned like PS agents to perform PDT in
tumor cells via the so-called Type I photoreaction mechanism,
Figure 52. Vascular targeted nanoparticles for imaging and photo- in which electrons were trapped at the QD surface and the
dynamic therapy treatment of brain tumors. (a) Schematic dwell time was long enough to promote electron transfer to
representation and characterization of a multifunctional nanoparticles.
(b) SEM images of those nanoparticles. (c) Monitoring of therapeutic
nearby oxygen molecules. Another study reported by Juzenas et
ecacy using multifunctional nanoparticles in 9L brain tumors by MR al. found that NIR photoactivation of QDs in cancer cells
imaging. (C1) A representative control of a mouse bearing a 9L results in the production of ROS and reactive nitrogen species
tumor; (C2) a tumor-bearing mice exposed to light only; (C3) iv (RNS) such as superoxide and peroxynitrite, respectively.395
administration of Photofrin plus laser light; (C4) nontargeted They employed dihydrorhodamine 123 as a sensor for the PDT
nanoparticles containing Photofrin plus laser light; (C5) targeted process, and found that ROS and RNS generated by QDs
nanoparticles containing Photofrin plus laser light. The image shown resulted in the breakage of lysosomes.
in (C6) was from the same tumor shown in (C5), which was treated To utilize the photostability of QDs and improve the
with the F3-targeted nanoparticle but at day 40 after treatment. (d) production of 1O2, several QDPS hybrids have been
KaplanMeier survival plot for the tumor-bearing mice after various
developed as a new generation of PS agents for PDT. In
treatments indicated. Reprinted with permission from ref 383.
Copyright 2006 American Association for Cancer Research. such hybrid QDPS systems, the excited singlet (1PS*) and
triplet (3PS*) states of PS drugs are indirectly generated by
nonradioactive energy transfer, also known as uorescence
carriers.386 In our latest work, PEGylated iron oxide nano resonance energy transfer (FRET). Because of the indirect
clusters (IONCs) were loaded with Ce6, obtaining IONC- photoactivation, photobleaching of PS drugs could be
PEG-Ce6 as a theranostic agent for dual-mode imaging guided minimized. The concept of FRET-based production of 1O2
and magnetic-targeting enhanced in vivo PDT387(Figure 53). by QDPS hybrid systems was also rst demonstrated by
Interestingly, Ce6 after being loaded on IONC-PEG exhibited a Samia et al.21 In their study, CdSe QDs with an average
red-shifted absorbance/excitation peak from 650 to 700 nm, diameter of 5 nm were linked to a silicon Pc photosensitizer
the latter of which located in the NIR region with improved (Pc4). In this system, the QD acted as the primary energy
tissue penetration. With strong magnetism of and long blood- donor if light with the wavelength between 400 and 500 nm
circulation time, IONC-PEG-Ce6 showed strong magnetic eld was used for excitation. Their results demonstrated that CdSe
(MF)-induced tumor homing ability, as evidenced by in vivo QDs could be used to sensitize either a PDT agent via the
dual modal uorescence and MR imaging. In vivo PDT FRET mechanism or molecular oxygen through a triplet energy
experiment using IONC-PEG-Ce6 under magnetic tumor transfer (TET) mechanism. Since then, many researchers have
targeting further demonstrated great therapeutic ecacy, explored a variety of covalent and noncovalent QDPS systems
achieving remarkably delayed tumor growth after just a single composed of CdSe, CdSe/CdS/ZnS, CdSe/ZnS, and CdTe
Figure 53. Magnetic targeting enhanced and NIR-induced in vivo PDT based on PEGylated iron oxide nanoclusters (IONC-PEG). (a) Schematic
illustration for the synthesis and structure of IONC-PEG-Ce6. (b) A schematic drawing to illustrate in vivo magnetic tumor targeting. (c) In vivo
uorescence image of a mouse bearing two 4T1 tumors after iv injection with IONC-PEG-Ce6. (d) In vivo T2-weighted MR images of a mouse
taken before injection (upper) and 24 h post injection (bottom) of IONC-PEG-Ce6. (e) Tumor growth in dierent groups after various treatments
indicated. (f) Representative photos of mice after various treatments. Reprinted with permission from ref 387. Copyright 2013 Elsevier.
QDs as energy donors, and various chromophores such as Fullerenes are found to be able to generate ROS upon
porphyrins, phthalocyanines, inorganic complexes, and other illumination, suggesting a possible role of them in PDT.397399
organic dyes as energy acceptors.389 As a typical example, Tsay As pristine fullerenes are highly hydrophobic, surfaces
et al. covalently conjugated Rose Bengal and Ce6 onto the functionalized with some functional groups attached to
surface of green- and red-emitting CdSe/CdS/ZnS QDs fullerenes are thus needed to make them more soluble in
through a lysine-terminated peptide linker396(Figure 54). By water and biological solutions. Phototoxicity of fullerenes has
using two color excitations, the conjugate could be simulta- been demonstrated in many studies. As early as in 1993,
neously used for uorescence imaging and singlet oxygen Tokuyama et al. used carboxylic acid-functionalized fullerenes
generation. in HeLa cells and demonstrated the phototoxic eect of
The intrinsic ROS production ability and excellent photo- fullerenes.400 Burlaka et al. used pristine C60 aggregates with
stability of QDs promise their use in PDT. Careful design of sizes of 10 m to induce phototoxicity in Ehrlich carcinoma
cells or rat thymocytes under irradiation by a mercury lamp.401
QD or QDPS conjugates to enable eective delivery of QDs
In another work, Yang et al. reported three C60 derivatives
and QDPS complexes into tumors, ecient generation of
attached with two to four malonic acid groups (DMAC60,
ROS, and image-guided PDT would be essential if QDs are
TMAC60, and QMAC60) as photodynamic agents to kill HeLa
employed in photodynamic cancer treatment. However, the cells.402
potential cytotoxicity of QDs containing heavy metal elements In vivo PDT for tumor treatment has also been
could be a majority obstacle toward the real clinical use of those demonstrated using fullerenes as the photodynamic agent.
nanoparticles in patients. Tabata et al. for the rst time demonstrated fullerene-based
3.2.5. Fullerenes and Their Derivatives. Fullerene, PDT of tumors in animal experiments.403 In this work, fullerene
discovered in 1985, is typically composed of 60 carbon atoms was functionalized with PEG, only not to acquire water
arranged in a soccer-ball structure. Fullerenes with 70, 72, 76, solubility, but also to enable preferential accumulation and
82, 84, and even up to 100 carbon atoms are also commonly prolonged retention of fullerene in the tumor tissue. As
obtained. The condensed aromatic rings present in fullerenes compared to the commercial agent Photofrin, C60-PEG
lead to an extended -conjugated system of molecular orbitals conjugate following intravenous injection oered a stronger
and therefore to signicant absorption of visible light. tumor suppressive eect under exposure to the visible light. In a
Figure 54. Singlet oxygen production by peptide-coated QD-photosensitizer conjugates for photodynamic therapy. (a) Scheme showing the
conjugation of Rose Bengal (RB) to peptide-coated QDs (pcQD) and the proposed mechanism for singlet oxygen generation via FRET. (b) UVvis
absorption spectra of 545 nm emitting pcQDs conjugated with RB at ratios of 1:1, 1:2, and 1:5. (c) Scheme showing the conjugation of Ce6 to
pcQDs and the proposed mechanism for singlet oxygen generation via FRET. (d) UVvis absorption spectra of Ce6-conjugated pcQDs and Ce6
alone (black). Reprinted with permission from ref 396. Copyright 2007 American Chemical Society.
later work by Tabata and coauthors, they introduced a excited with light with short wavelengths in the UV or blue
therapeutic and diagnostic hybrid system based on C60.404 regions, which has very limited tissue penetration. Future
After chemical conjugation of PEG to C60 to form C60-PEG, studies will include synthesis of new fullerene derivatives,
diethylenetridiethylenetriaminepentaacetic acid (DTPA) was particularly those with light-harvesting antennae to broaden the
subsequently conjugated to the terminal group of PEG to form range of activating light that can be used, hence increasing light
C60-PEG-DTPA, which was then mixed with gadolinium penetration depth into deep lesions.
acetate solution to obtain Gd3+-chelated C60-PEG (C60-PEG- 3.2.6. Other Nanocarbons. Other carbon nanomaterials,
Gd). Following iv injection of C60-PEG-Gd plus light including CNTs, graphene, and carbon dots, have also been
irradiation, the PDT ecacy was observed at the time when used for the delivery of PDT. In 2009, Naveen et al. reported
the tumor accumulation was detected by the Gd-enhanced T1- the direct observation of 1O2 production upon nonlinear
MR imaging, demonstrating the promise of using those excitation of SWNTs functionalized with COOH and/or
fullerene conjugates for cancer theranostic applications. In chitosan.22 It was demonstrated that 1O2 formation was
another study, Hamblin and coauthors uncovered that i.p. inuenced by several factors including surface functionaliza-
injection with mono(dimethylpyrolidinium) (BF4) fullerene tion/modication and the existence of residual iron catalyst.
1
and white light irradiation exhibited a signicant therapeutic O2 emission signals observed from SWNTs upon irradiation at
eect in a challenging mouse model of disseminated abdominal 532 nm were via a two-photon process. The relative quantum
cancer405(Figure 55). In this work, the tumor model was yield of 1O2 production at excitation wavelength of 532 nm was
generated by using engineered bioluminescent tumor cells. found to be 0.00, 0.070.13, and 0.240.53 for highly
Intraperitoneal injection of N-methylpyrrolidinium-fullerene functionalized, partially functionalized, and nonfunctionalized
formulated in cremophor-EL micelles followed by white-light SWNT samples, respectively. However, because surface
illumination delivered through the peritoneal wall (after functionalization usually is critical to develop SWNTs suitable
creation of a skin ap) produced a statistically signicant for bioapplications, it might not be that practical to use the
reduction in bioluminescence signals from the mouse abdomen, intrinsic photoinduced 1O2 generation ability of SWNT
and oered an obvious survival advantage in mice. samples in real PDT applications.
Fullerene derivatives have been demonstrated to be eective On the other hand, researchers have found that instead of
PS agents in photodynamic cancer treatment. However, the acting as a PS agent, SWNTs could in fact quench 1O2
major disadvantage of fullerenes in PDT is that they have to be generation of PS molecules attached to the nanotube surface.
Figure 55. Photodynamic therapy mediated by fullerene-based nanocarriers in a mouse model of abdominal dissemination of colon adenocarcinoma.
(a) Chemical structure of BF4 and chemical structure of photofrin. (b) UVvisNIR absorption spectra of BF4 in DMSO:water 1:9 (black solid)
and Photofrin in PBS (red solid), as well as uorescence emission spectra under broadband white (black dashes), green light (green dashes), and red
light (red dashes) excitations. (c) Bioluminescence imaging of CT26-Luc tumors growing in a representative control mouse (upper panel) and a
representative PDT treated mouse (lower panel). (d) Quantitative analysis of bioluminescence signals in control and PDT-treated mice showing the
inhibition of tumor development in mouse abdominal after treatment. Reprinted with permission from ref 405. Copyright 2011 Elsevier.
Figure 56. Regulation of singlet oxygen generation (SOG) using SWNTs. (a) A scheme showing the complex formed between a SWNT and
aptamer-photosensitizer (AP) conjugates for target controllable PDT. (b) The SOG signal of dierent samples. (c) The SOG signal plotted as a
function of thrombin concentration. (d) SOG specicity. Reprinted with permission from ref 406. Copyright 2008 American Chemical Society.
Zhu et al. designed a novel PDT system containing protein great quenchers to singlet oxygen generation (SOG), while in
binding aptamers, photosensitizers, and SWNTs.406 In their the presence of its target, the binding of target thrombin would
design, a photosensitizer was covalently attached to one end of
the DNA aptamer that wrapped onto the SWNT surface disturb the DNA interaction with SWNTs and cause the DNA
(Figure 56). In the absence of its target protein, SWNTs were aptamer to fall o from the SWNT surface, resulting in the
Figure 57. Photothermally enhanced photodynamic therapy delivered by nanographene oxide. (a) Schematic drawing showing Ce6 loading on
NGO-PEG. Red, Ce6; black, NGO; blue, six-arm PEG. (b) Scheme of the experimental design in photothermally enhanced PDT. Ce6 after being
loaded on NGO-PEG showed enhanced cellular uptake, which could be further promoted under mild photothermal heating of NGO induced by the
NIR light. Reprinted with permission from ref 123. Copyright 2012 American Chemical Society.
restoration of SOG.. Their results demonstrated that SOG GO-based nanocarriers to realize selective PDT of cancer
could be regulated by a target protein. cells.412,413
Several other teams have also studied CNT-based PDT In our work, we showed that PEGylated nano-GO could
delivery.407409 For example, in a recent work, Erbas et al. serve as a multifunctional nanocarrier to load photosensitizer
studied the use of noncovalent functionalized SWNTs as the Ce6 for photothermally enhanced PDT23(Figure 57). Again,
delivery agent for Bodipy-based PS agent in PDT.409 Pyrenyl- Ce6 was loaded on PEG-functionalized nano-GO via supra-
functionalized distyryl-Bodipy sensitizer was noncovalently molecular stacking. We found that the obtained nGO-
attached to SWNTs by stacking interactions, and was PEG-Ce6 complex oered a remarkably improved cancer cell
shown to generate singlet oxygen when excited at 660 nm with photodynamic destruction eect as compared to that of free
a red LED array. Ce6, due to the greatly increased cellular uptake of Ce6 when it
Graphene exhibits the unique 2-D structure and exceptional was loaded on nGO-PEG. More importantly, we showed that
physical and chemical properties, which lead to many potential the photothermal eect of nGO could be utilized to promote
applications including PDT. Dong et al. rst reported the the delivery of Ce6 molecules by a mild local heating when
graphene-based PDT.410 Zinc phthalocyanine (ZnPc), a widely exposed to a NIR laser at a low power density, further
used PS molecule, was loaded on the surface of nGO-PEG via enhancing the PDT ecacy against cancer cells.
stacking and hydrophobic interactions. They found that Carbon dots (C-dots) and graphene quantum dots (GQDs)
the obtained nGO-PEG-ZnPC exhibited signicant cytotoxicity with ultrasmall sizes have recently emerged as novel carbon
toward MCF-7 cells under Xe light irradiation. Cui and his co- nanomaterials showing great potential in nanomedicine and
workers reported the use of FA conjugated GO loaded with bioapplications. Several groups have explored their potential
Ce6 for folate-targeted PDT.411 Those nanocarriers could use as PDT agents. Chen and collaborators designed
selectively deliver Ce6 to MGC803 cells overexpressing the photosensitizer-conjugated C-dots for NIR uorescence
folate receptor, and achieve eective cancer cell photodynamic imaging guided PDT treatment.414 C-dots were employed for
destruction under the 633 nm laser irradiation. Several other improved PDT by two dierent excitation pathways: (1)
groups have also demonstrated the delivery of PS molecules by indirect excitation by FRET from the C-dots to Ce6; and (2)
Figure 58. Hypocrellin B (HB)-loaded gold nanocages (AuNCs) with high two-photon eciency for photothermal/photodynamic cancer therapy.
(a) Schematic illustration of the formulation of lipid-HB-AuNCs and the process of the combinational treatments of two-photon photodynamic/
photothermal therapy for suppressing tumor cell growth in a synergistic manner in vitro. (be) images of HeLa cells cellular uptake of lipid-HB-
AuNCs after 6 h incubation: (b) one-photon uorescent image of well-distributed lipid-HB in the whole cytoplasm; (c) two-photon luminescence
image of AuNCs scattered in the cytoplasm and on the membrane; (d) the overlapped image; and (e) xy top view at a given z and two other
images of the respective xz and yz side views along the green and red lines. (f) HeLa cell viability in vitro measured by MTT assay (n = 3) with
dependence on nanomedicine concentration. (g) HeLa cell viability in vitro measured by MTT assay (n = 3) under irradiation for dierent times.
(h) HeLa cell viability in vitro measured by MTT assay (n = 3) at dierent optical doses. (i) HeLa cell viability in vitro measured by MTT assay (n =
3) under dierent conditions. Reprinted with permission from ref 416. Copyright 2012 American Chemical Society.
direct excitation of the Ce6. Their results indicated that the therapy416(Figure 58). The hybrid conjugate comprised an
synthesized multifunctional nanocarrier platform was eective AuNC as a support core, mixed lipid layers with the
for enhanced PDT of gastric cancer tumor in vivo. In another incorporation of the two-photon photodynamic therapeutic
work, Trajkovic and collaborators studied cytotoxicity of GQDs agent hypocrellin B (HB), and a hydrophilic PEG shell. They
under light irradiation.415 They found that GQDs irradiated demonstrated that under two-photon illumination (790 nm
with blue light (470 nm, 1 W) could generate ROS including 85.5 pJ per pulse, 300s), the photodynamic anticancer
singlet oxygen, and were able to kill U251 human glioma cells treatment was dramatically enhanced by the photothermal
by causing oxidative stress. Their data indicate the potential eect.
usefulness of GQDs in PDT. MSNs have also been utilized as a nanocarrier for two-
3.2.7. Two-Photon Exciting Nanoparticles. Two-photon photon photodynamic agents. Gary-Bobo et al. prepared MSN
absorption (TPA) is the simultaneous absorption of two containing a porphyrin for ecient TPA-PDT in vivo.372 They
photons of identical or dierent frequencies to excite a demonstrated that a single intravenous injection with MSN-
molecule from one state (usually the ground state) to a higher mannose to nude mice (n = 4) bearing HCT-116 xenografts
energy electronic state. Using TPA materials, the window for was sucient to treat those tumors after two-photon irradiation
excitation can be extended into the infrared region, thereby at 760 nm for three periods of 3 min (Ti:sapphire laser
making the process more viable to be used to treat deep lesions. generating 150 fs wide pulses at a 76 MHz rate). Thirty days
Liang et al. constructed a new bioconjugate nanostructure by after treatment, PDT-treated tumors showed a remarkable
using photosensitizer-incorporated mixed lipid-coated AuNCs growth delay as compared to saline controls. In another work,
for two-photon photothermal/photodynamic cancer Cheng et al. demonstrated MSN coencapsulating TPA dyes and
Figure 59. Luciferase-immobilized quantum dots for self-illuminated photodynamic therapy. (a) Schematic representation of Renilla luciferase 8
(RLuc8)-immobilized QDs-655 for BRET-based PDT. (b) Relative tumor growth curves from dierent treatment groups. (c) Photos of A549
tumors taken from mice after various treatments. (d) H&E stained histological sections of tumors from dierent groups. Reprinted with permission
from ref 422. Copyright 2013 Elsevier.
photosensitizers could enable high-energy transfer rates for substrate for the PS immobilization.421 Upon the ionizing
two-photon activated PDT.417 By control of donoracceptor radiation, the scintillation nanoparticles could illuminate visible
(DA) ratios, the well-ordered mesoporous structure of MSNs light, which were then absorbed by PS molecules to generate
enhanced the energy transfer rate up to an unprecedented 93%. ROS. The utilization of scintillation nanoparticles for PDT has
They observed an ecient and controllable energy transfer several advantages as compared to traditional PDT and
mechanism via the facile modication of two-photon antenna radiation therapy, as in such a method the high-energy
molecules and photosensitizers on dierent topological radiation can penetrate deep tissues, and radiation doses can
domains in MSNs. The cytotoxicity induced by the singlet be markedly reduced from that needed for radiation therapy.
oxygen was demonstrated in both in vitro and in vivo breast Another approach is the development of self-illuminating
cancer models. By intratumor injection of nanoparticles to nude nanoparticles, which undergo the bioluminescence process and
mice bearing MDA-MB-231 breast tumors and then irradiation emit light from chemical energy to trigger PDT. Recently, Hsu
with a 920 nm femtosecond laser at a total energy of 150 J et al. developed Renilla luciferase-immobilized QD-655 (QD-
cm2, the death of cancer cell was examined by H&E stain and RLuc8),422 which was used for bioluminescence resonance
caspase-3 immunohistogram. energy transfer (BRET)-mediated PDT (Figure 59). When the
Two-photon excited PDT is able to increase the penetration substrate coelenterazine was added, the bioluminescent QD-
depth of the PDT illumination light in tissue and allow for RLuc8 conjugate exhibited self-illumination at 655 nm, which
treatment of thicker malignancies. However, this technique could activate the attached PS molecules. Both in vitro and in
requires the use of a pulsed laser as the light source to excite vivo results revealed the great potential for BRET-mediated
focused small areas to obtain sucient instant energy needed PDT using QD-RLuc8 conjugates without an external light
for two-photon excitation, and thus may have limited value for source for cancer therapy.
real clinical applications. The use of X-ray excited nanoparticles or self-illuminating
3.2.8. Scintillation Nanoparticles and Self-Illuminating nanoparticles to trigger PDT could circumvent the tissue
Nanoparticles. In PDT, because most of the PS molecules are penetration limit of light, which is the major disadvantage in
excited by visible light, the short light penetration depth has current phototherapies of cancer. However, the development of
been a major limitation. A few reports have explored some such techniques is still at its infant stage. The eciency of this
revolutionary PDTs strategies, which do not require external type of strategies may need further signicant improvement.
light irradiation. Scintillation nanoparticles such as LaF3:Ce3+, 3.2.9. Upconversion Nanoparticles for Near-Infrared-
LuF3:Ce3+, CaF2:Mn2+, CaF2:Eu2+, BaFBr:Eu2+, BaFBr:Mn2+, Induced Photodynamic Therapy. Upconversion nano-
and CaPO4:Mn2+ could emit visible luminescence upon particles (UCNPs) are usually lanthanide-doped nanocrystals,
exposure to ionizing irradiation such as X-ray, which shows which emit high energy photons under lower energy radiation
remarkably better tissue penetration ability as compared to (NIR light), and have shown potential applications in many
visible light.418,419 Liu et al. reported that LaF3:Tb3+-meso- dierent elds including biomedicine.102,423,424 As compared to
tetra(4-carboxy-phenyl) porphyrin (mTCP) nanoparticles traditional down-conversion uorescence, the NIR light excited
could be activated by X-ray irradiation with the energy upconversion luminescence (UCL) of UCNPs exhibits
transferred from LaF3+:Tb3+ nanoparticles to mTCP to improved tissue penetration depth, higher photochemical
generate ROS.420 Chen et al. also utilized scintillation stability, and is free of autouorescence background, making
luminescent nanoparticles (BaFBr:Eu +, Mn+)URE as a them widely explored new nanoprobes in biomedical imaging
Figure 60. Near-infrared light induced in vivo photodynamic therapy of cancer based on upconversion nanoparticles (UCNPs). (a) A schematic
drawing showing Ce6 physically adsorbed on the surface of PEGylated UCNPs via hydrophobic interactions to form a UCNPCe6 complex. (b)
The growth of 4T1 tumors on dierent groups of mice after various treatments indicated. (c) The survival curves of mice in 60 days after various
treatments indicated. A 980 nm laser at the power density of 0.5 W/cm2 was introduced for tumor irradiation. (d) Biodistribution of yttrium in
various organs of UCNPCe6 injected mice after PDT treatment. ICP-AES was employed to quantitatively determine the Y3+ levels. Reprinted with
permission from ref 25. Copyright 2011 Elsevier.
in recent years.99103,425429 Dierent from the two-photon photosensitizing nanoplatform for simultaneous PDT and
excited PDT, which requires the pulsed laser with high instant imaging.
energy as the excitation light and can only treat small areas The rst in vivo UCNP-based PDT study in animal
using the focused laser beam, continuous lasers with much experiments was demonstrated by our team25(Figure 60). In
lower instant energy densities can be applied to illuminate large our study, we noncovalently incorporated Ce6 onto PEGyla-
lesion areas in UCNP-based PDT. tedamphiphilic polymer-coated UCNPs. By directly injecting
Many groups have demonstrated in vitro PDT using UCNP- UCNP-Ce6 into 4T1 tumors grown on BABL/C mice, an
PS nanocomplexes.25,26,424,430432 In an early study by Zhang et obvious tumor regression eect was observed after tumors were
al., UCNPs were coated with a porous, thin layer of silica doped exposed to a 980 nm light at 0.5 W/cm2 for 30 min. Moreover,
with merocyanine-540 photosensitizer, and conjugated with a we found that UCNPs injected into tumors after PDT
tumor-targeting antibody for the targeted PDT to kill MCF-7/ treatment could be gradually cleared out from mouse organs
AZ breast cancer cells.26 Liu et al. used folic acid (FA) to after 2 months as determined by ex vivo inductively coupled
functionalized UCNP-RB nanoconjugates.431 A covalent plasma-atomic emission spectrometry (ICP-AES) assay. In a
bonding strategy was used to construct a highly ecient NIR side-by-side comparison experiment, we uncovered that the
Figure 61. UCNPs for in vivo tumor-targeted photodynamic therapy. (a) The uorescence emission spectrum of UCNPs under 980 nm NIR laser
excitation and the absorption spectra of ZnPc and MC540 photosensitizers. (b) A schematic drawing showing mesoporous-silica-coated UCNPs
coloaded with ZnPc and MC540 for PDT. (c) A schematic diagram showing UCNP-based targeted PDT in a mouse model of melanoma. (d)
Change in tumor size as a function of time after various treatments indicated. (e) Representative photos of mice from dierent treatment groups
before PDT and 7 days after PDT. Reprinted with permission from ref 430. Copyright 2012 Nature Publishing Group.
Figure 62. Multifunctional theranostic red blood cells for magnetic eld enhanced in vivo combination therapy of cancer. The scheme showing the
preparation steps of theranostic RBCs modied with IONPs, Ce6, DOX, and PEG. Reprinted with permission from ref 434. Copyright 2014 John
Wiley & Sons, Inc.
NIR-induced PDT using UCNPCe6 nanocomplex showed UCNP-based PDT based on systemic administration has also
much deeper tissue penetration in comparison to traditional been demonstrated in a few recent stud-
ies.390,392,395,430,432,435,436 Hyeon and co-workers reported an
visible light induced PDT when free Ce6 was used. A few other
in vivo PDT eect through the systemic administration of
groups have also demonstrated in vivo PDT using UCNP-PS UCNPCe6 followed by the 980 nm irradiation.430 In their
complexes by local administration.433,434 design, NaGdY4-based UCNPs after PEGylation were loaded
Figure 63. AuNR-photosensitizer complex for NIR uorescence imaging and photodynamic/photothermal therapy in vivo. (a) Schematic diagram of
the AuNRAlPcS4 complex for NIR uorescence imaging and tumor phototherapy. (b) Tumor-to-background ratio (TBR) determined by in vivo
NIR uorescence imaging at 1, 4, and 24 h post injection. (ce) In vivo PDT and PTT. (c) IR thermal images captured after 1 min of light
illumination, and (d) thermographic monitoring in the tumors of GNR-AlPcS4-injected and PBS-injected mice. (e) Tumor growth in dierent
groups of mice after various treatments indicated. Reprinted with permission from ref 457. Copyright 2011 American Chemical Society.
with Ce6 molecules by both physical adsorption and chemical layer (LbL) self-assembly strategy was employed to load
conjugation. Nude mice bearing U87MG tumors were injected multiple layers of Ce6 conjugated polymers onto UCNPs via
with UCNPCe6 through the tail vein. Obvious tumor electrostatic interactions. By further coating with an outer layer
accumulation of UCNPCe6 nanoparticles was revealed by of charge-reversible polymer, the obtained nanoparticles were
dual-modal upconversion luminescence imaging and T1- negatively charged and PEG coated under pH 7.4, and could be
weighted MR imaging. Under the 980 nm irradiation, tumor converted to have a positively charged naked surface at pH 6.8.
growth of UCNPCe6 injected mice was signicantly inhibited As the result, signicantly enhanced in vitro cell internalization
as compared to other control groups. In another recent study, and in vivo tumor retention of those nanoparticles were
Zhang and co-workers demonstrated in vivo tumor-targeted observed, leading to the remarkably improved NIR-induced
PDT using UCNPs loaded with dual types of PS molecules436- PDT ecacy both in vitro and in vivo. Our results suggest the
(Figure 61). In their study, UCNPs were coated with
great potential of tumor acidity-targeted in vivo dual modal
mesoporous silica and coloaded with ZnPc and merocya-nine
imaging and therapy using environmentally responsive nano-
540 (MC540), which were two widely used PS molecules with
dierent excitation wavelengths to allow full usage of the green agents.
and red emission light from UCNPs. After that, UCNPs were UCNPs with the unique upconversion optical properties
PEGylated and conjugated with folic acid for targeted PDT. have signicant potential in biomedical imaging and photo-
Mice bearing B16-F0 melanoma tumors were iv injected with therapy. However, there remain a number of challenges in this
ZnPc/MC540 coloaded FA-PEG-UCNPs and then irradiated eld. The low quantum yield of UCL emission of UCNPs (less
with a 980 nm laser at 4 h post injection. They found a than 1% for most of UCNPs) has been an important issue to be
signicant reduction in tumor growth of the treatment group as addressed. Better design of UCNP structure,437,438 and the use
compared to control mice treated with PBS. Gu and of upconversion nanocapsules based on triplettriplet
collaborators developed tumor targeted UCNP-PS nano- annihilation,439 may be helpful to promote the QY of
constructs with high ZnPc loading capacity for deep- UCNPs for more eective PDT. Moreover, the potential
penetrating PDT in vivo.435 Folate-modied amphiphilic toxicity and long-term fates of various types of UCNPs,
chitosan (FASOC) was coated on the surface of UCNPs to although having been investigated in a number of recent
anchor the ZnPc close to UCNPs, thereby facilitating reports,440442 still need to be better understood.
resonance energy transfer from UCNPs to ZnPc. In
3.3. Combination of Photodynamic Therapy with Other
comparison with conventional PDT depending on red light Therapeutic Approaches
irradiation, the NIR-induced PDT based on their nano-
constructs possessed higher tumor inhibition ratio for the Apart from being explored as a monotherapy of cancer, PDT
treatment of deep-seated tumors. could be integrated with chemotherapy, PTT, and some other
In our latest study, we developed charge-reversible Mn2+- treatment modalities for cancer combination therapy. The
doped UCNPs for pH-sensitive in vivo PDT.434 A layer-by- unique UCL emission of UCNPs under NIR light also has the
which were used together for combination therapy of tumors in

mice, showing an eective tumor regression eect after
treatment.444 A following work by the same group found that
the combination therapeutic eects could be signicantly
improved by conjugating the copolymer with an antibody to
allow higher tumor accumulation.447 After that, Peng et al.
demonstrated that the amphiphilic 4-armed star-shaped
chlorin-core diblock methoxy poly(ethylene glycol) (mPEG)
and poly(-caprolactone) (PCL) copolymers could form a
micelle structure, which could be utilized for the loading of
anticancer drug (paclitaxel) in the core via the hydrophobic
interaction. Using those micelles, an eective synergistic
treatment eect on MCF-7 cancer cells was observed.448
Recently, Khdair and co-workers prepared DOX and methylene
blue coencapsulated nanoparticles based on an anionic
surfactant (Aerosol-OT, AOT) and a naturally occurring
polysaccharide polymer (sodium alginate) via the multiple
emulsication cross-linking technique. The obtained nano-
particles were used for the treatment of multidrug resistance
(MDR) mouse tumor models, showing signicantly inhibited
tumor growth and improved animal survival after the combined
photodynamic and chemo-therapies.449
Additionally, various inorganic nanoparticles have also been
explored for combined chemotherapy and PDT.230,449451 In
2011, Wang and co-workers fabricated hematoporphyrin doped
hollow silica nanocages and used them for DOX loading. Those
nanoparticles with two types of therapeutic agents loaded were
robust in killing cancer cells by combining chemotherapy and
PDT.451 More recently, a work by Miao et al. indicated that
GO with PEGylation (pGO) could also be utilized for
simultaneously loading of DOX and Ce6. The fabricated
Ce6/DOX/pGO exhibited a superior antitumor eect in mouse
xenografts in comparison with those treated by Ce6/pGO or
DOX/pGO, respectively, under PDT treatment conditions.450
Besides systematic nanoparticle-based drug delivery systems,
red blood cells (RBCs) with inherent biocompatibility and long
systemic circulation represent an interesting class of drug
carriers. In a very recent work, our group developed a
Figure 64. Photosensitizer-loaded Au vesicles with strong plasmonic multifunctional drug delivery system based on RBCs for
coupling eect for imaging-guided photothermal/photodynamic magnetic eld (MF)-enhanced combination therapy of
therapy. (a) Scheme of Ce6-loaded plasmonic Au vesicles (GVs) for cancer452(Figure 62). In our design, IONPs coated with PS
triple modal uorescence/thermal/photoacoustic imaging guided molecules, Ce6, are attached onto the membrane of RBCs, in
synergistic photothermal/photodynamic cancer therapy. (b) In vivo
which a chemotherapy drug DOX is loaded. After further PEG
NIR uorescence image of MDA-MB-435 tumor-bearing mice taken at
pre injection and post injection of GV-Ce6. (c) IR thermal images of coating, we obtained DOX@RBC-IONP-Ce6-PEG with long
tumor-bearing mice exposed to 671 nm laser (2.0 W/cm2) for 6 min at blood circulation time and strong responses to the external MF.
post injection of GV-Ce6. (d) Tumor growth curves of dierent Those theranostic RBCs were then used for in vivo MF-
groups of tumor-bearing mice after dierent treatments. Reprinted enhanced cancer treatment in a mouse tumor model using
with permission from ref 56. Copyright 2013 American Chemical rather low doses of therapeutic agents, achieving a great
Society. synergistic tumor growth inhibition eect after the combined
photodynamic and chemotherapy is conducted. This work
potential to be employed to trigger a few other therapeutic highlights the promise of a smartly designed RBC-based drug
mechanisms (Table 2). delivery system as a safe and multifunctional platform for
3.3.1. Combination of Photodynamic Therapy with combination therapy of cancer.
Chemotherapy. The combination of PDT with chemotherapy 3.3.2. Combination of Photodynamic Therapy with
has a long histology in both preclinical research and clinical Photothermal Therapy. Recently, NIR-absorbing nanoma-
tumor treatment applications.443,444 Many polymer-based drug terials, which could simultaneously work as the photosensitizer
delivery systems that are capable of delivering both chemo- carrier and as heat generator, have been explored to combine
therapy drugs and photodynamic PS molecules have been PDT with PTT together for synergistic cancer killing.123,453 As
widely explored by dierent groups.445,446 As an early example, described in detail in the earlier part of this Review, our group
in 1996, Peterson and co-workers synthesized N-(2- demonstrated the use of PEGylated nano-GO with Ce6 loading
hydroxypropyl)methacrylamide (HPMA) copolymer-Adriamy- for photothermally enhanced delivery of PDT.123 After that,
cin conjugate and HPMA copolymer-meso-chlorin e6 mono- Sahu and co-workers indicated that Pluronic block copolymer
ethylene diamine disodium salt (Mce6) conjugate, both of functionalized GO could also be utilized for the loading of
methylene blue via the electrostatic interaction. The obtained a large variety of research groups, as well as photodynamic
nanocomplex exhibited a superior synergistic anticancer eect therapeutic approaches relying on dierent mechanisms by
in mouse xenografts when used in combination with PTT.454 utilizing the unique properties of functional nanostructures, are
More recently, Wang and co-workers prepared a multifunc- summarized in detail. Explorations regarding the combination
tional nanoplatform by covalently grafting GO with UCNPs, therapy of cancer by integrating phototherapeutic methods with
obtaining GO-UCNP composite, which was demonstrated to other traditional therapies to achieve the synergistic cancer
be eective for the loading of photosensitizer ZnPC to realize a killing eect are further discussed. However, despite the
synergistic treatment eect of cancer cells in vitro by combining tremendous amount of exciting results reported in the past
PTT with PDT.455 Besides, Wang and colleagues fabricated an few years in this eld, there are still many challenges ahead
aptamer switch probe conjugated AuNRs for the targeted toward further clinical applications of those functional nano-
delivery of Ce6 and observed a synergistic therapeutic eect of materials in phototherapies of cancer.
cancer cells under combined treatment with both PDT and (i) One of the most important issues is the potential long-
PTT.456 In another piece of work by Jang and cowaorkers, it term safety concerns of the nanomaterials, especially those
was demonstrated that Al(III) phthalocyanine chloride inorganic ones that are not biodegradable and would retain
tetrasulfonic acid (AlPcS4) loaded AuNRs could contribute inside the body for long periods of time after administration.
to a strong reduced tumor growth eect (95% inhibition) in Although a large number of reports have demonstrated that
mouse xenografts after being combinedly treated with PDT and many inorganic nanomaterials, such as gold and carbon
PTT, while the tumor growth inhibition eect was 79% for nanomaterials, if with appropriate surface coatings and sizes,
those only receiving PDT treatment457(Figure 63). are not noticeably toxic in vitro and in vivo in the tested dose
In the above-mentioned studies, two dierent lasers are ranges, it could still be extremely tough for those nanoagents to
independently used to trigger PDT and PTT separately. For nally get FDA approval for clinical use. The recent preliminary
operation convenience and patient comfort, it would be helpful success in the clinical trial of gold nanoshells would shine some
to nd new strategies to realize combined PDT and PTT under light on this direction though. Nevertheless, the development
a single laser irradiation. In 2008, Zhang et al. fabricated BSA of biocompatible and biodegradable nanoagents for photo-
stabilized single-wall carbon nanohorns (SWNHs) with holes thermal and photodynamic therapy of cancer could thus have a
opened for the photosensitizer (ZnPc) loading. The obtained much higher clinical value.
nanocomplex oered greatly improved therapeutic eects by (ii) Another major challenge in phototherapy of cancer is the
combining PDT and PTT under the irradiation of a 670 nm limited light penetration depth. For photothermal therapy, NIR
laser both in vitro and in vivo, in comparison single PDT or absorbing photothermal agents are absolutely preferred over
PTT therapy delivered by ZnPc or SWNHs alone, those with visible absorption considering the reduced light
respectively.458 Similarly, by using the photosensitizers (e.g., absorbance and scattering in the NIR window. Regarding
ICG, Ce6) with strong absorption in NIR region, several photodynamic therapy, the visible light used in traditional PDT
interesting works have demonstrated that various NIR- is not the ideal light source. Although progress has been made
absorbing nanostructures (e.g., AuNRs, AuNFs) could be in the development of NIR-induced PDT (e.g., by using
used for photosensitizer delivery and showed excellent UCNPs or two-photon excitation PDT agents), great eorts are
synergistic therapeutic eects under the single wavelength still required to develop new generations of PDT agents that
laser irradiation.453,459,460 More recently, Lin and colleagues can be more eectively excited by the NIR light.
fabricated a Ce6 loaded gold vesicle with strong NIR light (iii) Even if NIR light is used to trigger phototherapy, the
absorbance in the NIR region of 650850 nm. Using this eective penetration depth of NIR light is still usually limited to
nanoagent upon intratumoral injection, eective combined be no deeper than 1 cm. For some types of cancers, such as skin
PDT and PTT under the 671 nm laser irradiation was achieved, cancers, oral cancer, esophageal cancer, and even stomach
resulting in remarkable tumor regression after treatment56- cancers, light can be induced to locally irradiate the tumors with
(Figure 64). By utilizing the two-photon technique, Gao et al. the help of certain facilities (e.g., gastroscopy, endoscopy). For
prepared a lipid-coated AuNC for the delivery of a photo- other types of cancers with tumors located deeply inside the
sensitizer (hypocrellin B), achieving eective cancer treatment body, eective phototherapy would require the appropriate
eect by combined PDT and PTT.461 Apart from utilizing the design of medical devices (e.g., with optical bers) that can
inorganic NIR-absorbing nanostructures as the heat generator deliver light into those deep lesions. Moreover, it would be
for combined PDT and PTT, Peng and colleagues exploited a greatly benecial for clinicians if some imaging functions can be
traditional hydrophobic photosensitizer (phthalocyanine, PC) integrated into such medical devices to real-time track the
with a strong NIR light absorption as both ROS and heat location of phototherapeutic agents, to ensure all of the tumor
generator for combined PDT and PTT after being loaded in mass is eectively exposed to the light, and to monitor the
hollow silica nanoparticles (HSNs).462 It was found that the as- therapeutic responses at the real time (e.g., temperature
prepared PC-HSNs exhibited an eective combined therapeutic elevation of the tumor and its surrounding tissues during
eect both in vitro and in vivo after being irradiated with a 730 photothermal therapy). Such phototherapy medical devices, if
nm laser, showing an outstanding potential for further designed by a team with experts from dierent backgrounds,
exploration of the new-generation combination therapy for may greatly promote the development of phototherapy in
cancers. clinical cancer treatment.
(iv) Dierent from traditional chemotherapy, phototherapy
4. FUTURE CHALLENGES AND PROSPECTS uses light to locally irradiate the tumor. Therefore, imaging-
In this Review, we have systematically reviewed the recent guided therapy becomes extremely meaningful and important
advances in phototherapies of cancer using functional nano- in phototherapy: (1) Before phototherapy, careful whole-body
materials. Photothermal therapy studies based on various imaging should be carried out to nd out the exact tumor
inorganic and organic NIR-absorbing nanoagents reported by location, size, and shape, to ensure the ecient light exposure
of the whole tumor. (2) To achieve the highest photo Biographies

therapeutic ecacy, the light irradiation has to be applied when
the phototherapeutic agent reaches the highest accumulation in
the tumor, as the tumor homing of any agent is a dynamic
process. Thus, the real-time track of the phototherapeutic agent
after administration by imaging is important to achieve the
optimized therapeutic outcome. (3) After treatment is
accomplished, advanced imaging techniques are required to
determine the therapeutic response as early as possible. In this
regard, it would be ideal if a phototherapeutic agent could also
have the imaging capability. Therefore, a well-engineered
nanoplatform that oers both therapy and imaging function-
alities could have important clinical values and be of great
interest to the future development of phototherapies. Dr. Liang Cheng received his Ph.D. degree from the Institute of
(v) Each therapeutic approach could have its own advantages Functional Nano & Soft Materials (FUNSOM) at Soochow University
and limitations. Although phototherapy does have its great in 2012. His Ph.D. thesis was focused on the biomedical applications
of upconversion nanoparticles under the supervision of Prof. Zhuang
potential, it is still not realistic to expect that phototherapy by Liu. He is now an associate professor in Prof. Lius group. His current
itself would win the ght against cancer. There is almost no research interest is the development of multifunctional nanostructures
doubt that future cancer therapies would very much likely rely for applications in cancer theranostics, partially for imaging-guided
on the combination of a set of dierent treatment approaches, photothermal therapy of cancer.
which may include surgery, chemotherapy, radiotherapy, gene
therapy, as well as photothermal and photodynamic therapies
discussed in this Review. Therefore, the development of
multifunctional nanocarriers that enable dierent therapeutic
mechanisms for cancer combination therapy may bring great
opportunities to the new generation of cancer therapy.
Besides the above-mentioned challenges and prospects, there
are also a number of in-depth basic mechanism questions that
remain to be addressed in the future development of
phototherapy for cancer treatment. For example, how the
immune system would respond to photothermal or photo-
dynamic killing of tumor cells, what would be the eect of the
tumor residues after photothermal ablation, what could be the Chao Wang was born in Jiangsu, China, in 1987. He received his B.S.
degree from Soochow University in 2010. Since then, he has studied as
most optimized therapeutic condition for photodynamic
a Ph.D. candidate under the guidance of Prof. Zhuang Liu in
therapy in which oxygen is involved, and how to realize the FUNSOM at Soochow University. His current research directions
most eective synergistic eect when phototherapy is combined include photodynamic therapy based on UCNPs and the applications
with other therapeutic methods all merit further careful of UCNPs for cell tracking and cell therapies.
investigations. Moreover, whether phototherapy would bring
any potential therapeutic advantages to overcome multidrug
resistance of tumor cells and prevent tumor metastasis, which
are two killing factors of cancer, would be of great importance.
Nevertheless, it is believed that phototherapies based on
functional nanoagents, due to their unique advantages such as
minimal side eects and high ecacies, would play increasingly
important roles in the ght against cancer.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zliu@suda.edu.cn.
Liangzhu Feng received his B.S. degree from Soochow University in
Notes
2010. Since then, he has been pursuing his Ph.D. degree at FUNSOM
The authors declare no competing nancial interest. of Soochow University under the supervision of Prof. Zhuang Liu. His

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Review

Functional Nanomaterials for Phototherapies of Cancer

10877 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

uptake of RGD-dAuNRs over time. They further observed the

10878 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

benecial for the treatment of relatively large tumors without

Like CNTs, GO without surface coating after intravenous

metal dichalcogenides (TMDCs), such as MoS2, MoSe2, WS2,

10894 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

Table 2. A Summary of Functional Nanomaterials Developed for Combination Therapy

injection of IONC-PEG-Ce6 and 704 nm NIR light exposure at

which were used together for combination therapy of tumors in

of the whole tumor. (2) To achieve the highest photo Biographies

10931 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

research interest is focused on the light-controllable drug and gene REFERENCES

10932 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

10933 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

10934 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

10935 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

10936 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

10937 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

10938 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

10939 dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 1086910939

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