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Advances in Colloid and Interface Science xxx (2013) xxxxxx
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Advances in Colloid and Interface Science

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Gold nanoparticles: A paradigm shift in biomedical applications

Mohammed S. Khan a,, Gowda D. Vishakante a, Siddaramaiah H b
a
Dept. of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore 570015, India
b
Department of Polymer Science and Technology, Sri Jayachamarajendra College of Engineering, Mysore 570 006, India
a r t i c l e i n f o a b s t r a c t
Available online xxxx In the medical eld, majority of the active ingredients exists in the form of solid particle (90% of all medicines).
Nanotechnology had grabbed the attention of many scientists working in different aspects and gave them a vivid
Keywords: imagination in order to utilize the nanotechnology in an innovative way according to their needs. One of the
Gold nanoparticles major applications of nanotechnology is drug delivery through nanoparticles which is on boom for the re-
Cancer therapy searchers and gives a challenging environment for the researchers. Among them upcoming challenge is the
Computed tomography
use of inorganic nanoparticles for the drug delivery and related aspects. There is growing interests in usage of in-
Biomedical applications
organic nanoparticles in medicine due to their size, and unique physical properties that make them different
from other nanoparticulate systems. This review will lay special emphasis on the uniqueness of inorganic
nanoparticles especially gold nanoparticles as a drug delivery vehicle and moreover will present a wide spread
scenario of gold nanoparticles that has been used for treatment of life threatening diseases like cancer.
2013 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Synthesis of gold NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. Gold nanospheres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. Gold nanorods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3. Gold nanoshells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.4. Gold nanocages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Properties of gold Nps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.1. Optical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.2. Multifunctional behavior of gold NPs for biomedical therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.3. Gold NPs for molecular imaging in cancer therapy and other related diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.4. Role of gold NPs in deep tissue imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4.5. Surface enhanced Raman scattering (SERS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. Radioactive isotopes of gold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6. Role of gold NPs in DNA plasmid studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7. Gold nanoparticles as an antioxidant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
8. Gold nanoparticles as biosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
9. Toxicity related aspects of gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1. Introduction the size and shape at a nanometer scale [1]. As a forthcoming eld nano-
technology is about to bring fundamental changes in manufacturing
Nanotechnology can be dened as the design, evaluation, produc- and will make a huge impact on every aspect of life sciences namely
tion and application of structures, devices and systems by controlling drug delivery, diagnostics, neutraceuticals and production of biomate-
rials as well as on electronics. Developing newer molecules and manip-
Corresponding author at: Dept. of Pharmaceutics, JSS College of Pharmacy, JSS
ulating those available naturally in nanosize could be appealing for their
University, Mysore 570015, Karnataka, India. Tel.: + 91 8088054966. greater potential to improve health care [2]. Several pharmacological
E-mail address: mshuaibkhan68@gmail.com (M.S. Khan). sectors have got approval from the Food and Drug Administration
0001-8686/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.cis.2013.06.003
Please cite this article as: Khan MS, et al, Gold nanoparticles: A paradigm shift in biomedical applications, Adv Colloid Interface Sci (2013), http://
dx.doi.org/10.1016/j.cis.2013.06.003
2 M.S. Khan et al. / Advances in Colloid and Interface Science xxx (2013) xxxxxx
(FDA) for the use and development of nanotechnology-based drugs in oscillation. Detection of biological events at the single molecule
the last few years. Well dened knowledge of the fundamental relation- level has been used for biosensing by exploiting the distance-
ships would allow nanoparticles (NPs) to be fabricated with denite dependent scattering properties of the AuNPs. Upon getting excited
size and surface characteristics and/or modied for delivery to specic plasmon resonance band can be spectrally modied over a wide
cells or organs in the body. Over the past few decades, advances in range. The outcome is that the sense of light scattering signal is
nanotechnology have spurred development in many biomedical appli- more profound (highly intense) and comparatively much brighter
cations including cancer therapy, drug delivery and as biomarkers in than the chemical uorophores. This property can be useful in imag-
imaging techniques. Many nanoparticle based drug delivery systems ing techniques i.e., single molecule imaging can be achieved [20,21].
have been designed in order to fulll the ever growing need of the sci- Recently there has been an explosion in gold NP research, with a
ence in both medical as well as in pharmaceutical elds. Latest techno- rapid increase in gold NP publications in diverse elds including im-
logical advancements have brought many new innovative drug delivery aging, bioengineering and molecular biology. It is probable that this
systems into commercialized forms. The most targeted area of contem- relates to a similar increase in the broader eld of nanotechnology, in-
porary research using nanoparticles especially focuses on targeted drug creased governmental awareness and funding, and rapid progress in
delivery at intracellular level in order to combat life threatening dis- chemical synthesis and molecular biology [22].
eases. Over the years, scientist has achieved better insights into gold
NP systems and is in continuous run in order to better establish the 3. Synthesis of gold NPs
use of gold NPs in all sectors of pharmaceutical therapy as a major
drug delivery approach. The synthesis or production of nanoparticles follows the same
This review focuses on the gold nanoparticles (AuNPs) that prove fundamental rule i.e., reduction of size (top-down technique). Gold
to be an important tool for a number of biomedical applications like NPs can be produced by reduction of gold salts in the presence of sta-
drug delivery, imaging and treatment of major life threatening dis- bilizing agents in order to prevent agglomeration. The gold NPs can be
eases. Functional metallic nanomaterials have gained much attention prepared in three different methods:
from the researchers not only as a drug delivery vehicle or diagnostic
tracer tool but also as an optical carrier. Recently, gold has gained (i) Physical methods like microwave (MW) irradiation, sono-
much more attention and tremendous works have been done due to chemical method, ultra violet (UV) radiation, laser ablation,
its unique therapeutic activity, inert and nontoxic nature. In past thermolytic process and photochemical process [2327].
few years scientist had explored gold as a major drug delivery tool (ii) Chemical methods employ the use of chemical reactions like
which not only provides therapeutic benets but also acts as a tracer the generation of gold NPs in an aqueous medium using citrate
for diagnostic imaging which will give structural information on or sodium borohydride as a reducing agent. However, it is well
very molecular level. Various researchers had prepared gold particles reported that if citrate concentration is well controlled small
in different shapes and sizes for targeting many diseases. The use of and uniform size gold NPs can be produced [2830]. Melissa
gold particles not only offers many advantages for the researchers synthesized gold NPs by reducing gold (IV) chloride (AuCl4)
for biological actions but also provides a possibility of imaging a sin- and sliver nitrate (AgNO3) using heparin and hyaluronan, as
gle particle deep inside the body tissue by various imaging techniques reducing and stabilizing agents respectively. Produced NPs
which not only target specic cells (e.g.: tumor cells) but also open a showed good stability under physiological conditions [31].
window for gene therapy. However, inspite of numerous works done Most advantageous of gold NPs is that they can be easily func-
on gold particles, having exact control on intracellular delivery and tionalized or modied by tagging the thiol linkers in their
intracellular localization of NPs remains a major challenge and con- monolayers. The surface modication of AuNPs can be easily
tinuous research works are in progress in order to give a clear-cut in- carried out with peptides, proteins, oligosaccharides, and
formation. In this review we focused on most latest biomedical nucleic acids [3138]. The use of an inorganic matrix as a sup-
applications and clinical advances of gold nanoparticles. The applica- port or host to produce the nanoparticles is another way to pro-
tions of gold in cancer therapy, as a diagnostic and imaging tool, and duce gold NPs. Mukherjee et al. had used silica supported
the role of gold in DNA model studies, as an antioxidant and as bio- surface which contains a silanol group that helps to reduce
sensors had been widely discussed. chloroaurate ion to gold NPs [39].
(iii) Another way to produce NPs is the supercritical uid technolo-
2. Gold nanoparticles gy. A supercritical uid can be generally dened as a solvent at
a temperature and pressure above its critical point, at which
Looking in the past, gold has been already reported as a health ad- the uid remains a single phase regardless of pressure [40]. Su-
juvant. Chinese and Indian culture reported the use of gold com- percritical CO2 (SC CO2) is the most widely used supercritical
pounds in the form of Swarna Bhasma for treatment of various uid because of its mild critical conditions (Tc = 31.1 C,
health needs like increasing vital power and curing male impotence Pc = 73.8 bars), non-toxicity, non-ammability, and low cost.
[35]. Its unique properties like inertness, nontoxic nature towards The most common processing techniques involving supercriti-
cell and biocompatibility of gold make it useful and attractive mate- cal uids are supercritical anti-solvent (SAS) and rapid expan-
rials for the researchers for biological and biomedical applications as sion of critical solution (RESS). The process of SAS employs a
well as relevant in therapy and imaging [617]. liquid solvent, e.g., methanol, which is completely miscible
Myocrism (sodium aurothiomalate) and Solganol (auro- with the supercritical uid (SC CO2), to dissolve the solute to
thioglucose) are water soluble gold complexes present which show the micronized; at the process conditions, because the solute
benecial effect in rheumatoid arthritis. Earlier in 1978 cisplatin is insoluble in the supercritical uid, the extract of the liquid
was approved by the Food and Drug administration (FDA) as an solvent by supercritical uid leads to the instantaneous precip-
antitumor agent. This nding opens a new gate for the researchers itation of the solute, resulting in the formation of NP. Thote and
to investigate and explore deeply, using gold NPs as an antitumor Gupta reported the use of a modied SAS method for the for-
agent. It was found that the combination of gold (I) and gold (III) mation of hydrophilic drug dexamethasone phosphate drug
complexes enhanced the antitumor activity of known antitumor com- NP for microencapsulation purpose [41]. Supercritical uid
pound [18,19]. technology also helps to prepare lanthanides such as europium
Gold NPs have the tendency to absorb and scatter visible and near (Eu), yttrium (Y) and gadolinium (Gd), and transitional metal
infrared (NIR) light resonantly upon excitation of surface plasmon based nanoparticles [42].
dx.doi.org/10.1016/j.cis.2013.06.003
M.S. Khan et al. / Advances in Colloid and Interface Science xxx (2013) xxxxxx 3
Fig. 1. Different types of gold NPs with their shapes.
(iv) Biological methods are like the use of fungus or bacteria as a adsorption of the PDMA block on the surface of gold nanoparticles
source can be used to produce NPs [43,44]. Biological methods whereas PMPC functions as a stabilizing block, which ultimately results
to produce gold NPs have been used as an alternative in order in highly biocompatible gold sols in an aqueous solution without any
to avoid the use of organic solvents that have been used in external reducing agent.
chemical and physical processes, thus making biological pro-
cess an eco-friendly approach for the production of gold NPs. 3.2. Gold nanorods
Different types of gold NPs had been shown in Fig. 1.
Gold nanorods have received much attention as a drug delivery
3.1. Gold nanospheres vehicle due to its low cytotoxicity, excellent stability, biocompatibility
and suitable physiochemical parameters. Numerous works had been
Gold nanospheres also referred as gold colloids and their size lie in done using gold nanorods as a drug delivery adjuvant. As reported
the range of 2 nm100 nm and can be synthesized by controlled re- by Martin et al. [50] and van der Zande et al., [51] gold nanorods
duction of an aqueous solution of HAuCl4 using a reducing agent can be synthesized using a template based method i.e., electrochem-
(ex: citrate). The particle size of gold NPs can be easily controlled ical deposition of gold in pores of a polycarbonate or an alumina
by varying gold to reducing agent ratio. It is well documented that based template membranes.
the small amount of citrate will yield large sized nanospheres [45], a Xu et al. prepared gold nanorods using the seed-mediated template-
two phase method which can produce stable gold nanospheres, assisted procedure by reducing gold salt in the presence of surfactant-
with reduced dispersity and well-controlled size. Most of all these directed synthesis and investigated the benet of combining RGD-
reported the use of the NaBH4 as reduction of HAuCl4 in the presence conjugated gold nanorods (RDG-GNRs) that target integrin with
of any thiolated ligand (tetraoctylammonium bromide, TOAB) irradiation in melanoma cancer cells and concluded that RGD-GNRs
[46,29]. This method was also optimized to produce nanospheres of could sensitize melanoma A375 cells to irradiation as shown in Fig. 3
small size. Manipulating the thiol/gold ratio and a quicker addition [52,53]. Murphy and Jana [54] had reported the wet chemical synthesis
of a reducing agent in cold solution will produce gold nanospheres of monodisperse gold nanorods with high aspect ratio. The method in-
of smaller size with good dispersity. volves the surfactant directed growth of nanorods from spherical seeds.
Leff et al. [47] have investigated on the amine-capped gold It was reported that gold nanorods of aspect ratios of 4.6 1.2, 13 2
nanocrystals with diameter of 2570 . All physical characterizations and 18 2.5 have been developed using the above method. The only
that had been carried-out are consistent with a charge-neutral amine/ disadvantage of this method is, gold nanorod yield was found to be
gold surface interaction described by a weak covalent bond. The low as it was difcult to separate gold nanorods from other different
obtained data indicates that the stability of gold nanocrystals pro- shaped gold side products that were formed in the reaction.
duced was stable and appears to be kinetic rather than thermody- The length and diameter of nanorods have to be determined and it
namic, in nature. is completely dependent on the pore diameter of template membrane
Lauren et al. [48] synthesized gold NPs by reducing HAuCl4 with so- whereas length can be controlled by keeping a check on the amount
dium citrate and found that the obtained NPs are stable and highly-pure of gold deposited within the pores of template membrane. However,
and were used as a probe to transport of cleavage-stage zebrash em- a major limitation of production of gold nanorods is its yield. A low
bryos in order to assess the effects on embryonic development. Yuan yield is found since only one single monolayer nanorod is prepared.
et al. [49] documented the use of biocompatible block copolymers Formation of gold nanorods through electrochemical routes has
(poly(2-methacryloyloxy) ethyl phosphorylcholine) (PMPC) block been studied. Chang et al. [55] used an electrochemical method to pre-
and a poly(2-(dimethylamino) ethyl methacrylate) (PDMA) for the pare an aqueous solution containing gold nanorods. The effects of wave-
synthesis of sterically stabilized gold nanospheres in an aqueous solu- length, laser uence and matrix content on the size, shape, purity and
tion as shown in Fig. 2. This research study proved to be useful in the yields of nanorods have been studied. Reetz et al. [56] had used
Fig. 2. Schematic representation of adsorption of the PDMA block on the surface of gold nanoparticles.
dx.doi.org/10.1016/j.cis.2013.06.003
Fig. 3. Schematic representation of preparation and conjugation of gold nanorods (RDG-GNRs).
electrochemical method for size selective preparation of tetraalkyl am- Oldenburg and coworkers [61] were rst to develop silica-core
monium salt stabilized clusters in a size range of 16 nm. This method gold nanoshells, a new frequency-agile nanoparticles. Basically a
possesses advantages of high yield, easy isolation and simple control four step synthesis procedure had been reported. The rst step aims
of particle size of nanorods. to develop monodisperse silica nanoparticles using the Stober meth-
Several other methods had been employed to prepare nanorods of od to produce the spherical dielectric cores. The second step indulges
desired size and shape. Canizal et al. [57] developed nanorods by the functionalization of silica nanoparticles by the adsorption of an
bioreduction methods. Sharma et al. [58] reported the use of centrifu- organosilane (3-aminopropyltriethoxysilane), with its amine tails
gation techniques for excellent separation of colloidal gold nanorods coming out from the surface. The third step is to coat the silica NPs
from a mixture of nanorods and nanospheres. It is well reported in by a colloidal solution of gold (12 nm in diameter). Finally reduction
that the hydrodynamic behavior of nanorods and nanoparticles be- takes place to produce silica NPs covered with a uniform coat of gold
haves differently. It is concluded that shape-dependent drag causes thus nally producing a gold nanoshell.
particles to have shape-dependent sedimentation behavior which
will give an ease of separation of nanorods. 3.4. Gold nanocages
Nidome et al. [59] had prepared nanorods for drug delivery appli-
cations. Plasmid DNA was rst absorbed onto PC-modied gold Gold nanocages are hollow porous gold NPs, size basically ranges in
nanorods by electrostatic interaction and from that release was tested between 10 and 150 nm and consists of hollow interiors and porous
by illuminating the PCnanorodDNA solution with the fundamental walls. They are generally produced by silver nanoparticles with
light of a Q-switched Nd:YAG laser. DNA release was conrmed by gel chloroauric acid (HAuCl4) in boiling water. The nanocages are prepared
electrophoresis. by simple galvanic replacement reaction which occurs between solu-
tions containing metal precursor salts and Ag nanostructures. The
differences in electrochemical potential control the whole reaction ulti-
3.3. Gold nanoshells mately depositing the reduced metal on the surface of gold nanostruc-
ture [62]. When it comes to the size of nanocages these can be easily
Nanoshell or generally called as nanoshell plasmon, is nothing but controlled by adjusting the molar ratio of silver to HAuCl4. Other fea-
another name given to nanoparticles which have a dielectric core tures that make gold nanocages an exciting approach are their compact
covered by thin metallic shell over it (more specically gold). These sizes, large absorption cross sections, bio-inertness and ability for sur-
nanoparticles engage a quasiparticle (emergent phenomena that take face modication based on Au-thiolate chemistry [63].
place when solid behaves like weakly interacting particles in free
space) called plasmon which is a quantum of plasma oscillation where 4. Properties of gold Nps
electrons concurrently oscillate with respect to ions that are present
[60]. Gold nanoshells are spherical NPs with diameters ranging in size 4.1. Optical properties
from 10 to 200 nm. As novel nanostructures, they possess a remarkable
set of optical, chemical and physical properties, which make them ideal Inorganic NPs offer researchers a exible approach to make use of
candidates for enhancing cancer detection, cancer treatment, cellular NPs according to their use and needs. Adjustment of optoelectronic
imaging and medical biosensing. They can be easily modied to properties due to the shape and size of inorganic NPs makes them dif-
absorb/scatter light at specic wavelengths in the visible and near- ferent from other NP systems and applicable for various biomedical
infrared (NIR) regions of the spectrum [47]. applications. Gold NPs due to its brilliant color and unique properties
dx.doi.org/10.1016/j.cis.2013.06.003
are highly suitable for biomedical applications. Gold NPs possess a instillation period of 1 h only, gold NPs appeared in lung macro-
strong surface plasmon resonance (SPR) band that totally depends phages. It was found that only a tiny fraction of the gold NPs is
on particle size, shape and dielectric strength of the metal and the translocated in systemic circulation and translocation rate was
surrounding medium [6467,42]. Susia and El Sayed [68] explained greatest with the 2 nm gold particles and they get accumulated in
the phenomena of SPR clearly. Free electrons in the metal (d elec- the liver.
trons) will travel through a mean path (mean free path 50 nm) thus The promising potential of AuNPs in the treatment of inammatory
particle less than 50 nm will not get scattered from the bulk rather and autoimmune diseases has augmented greater interest to researchers
the interaction will happen on the surface that will help in scattering. in order to evaluate the anti-oxidative and anti-hyperglycemic activity
Thus when the wavelength of light is larger than the particle size it of the gold nanoparticles in the diabetic patients. The inhibitory activity
will switch over the charge and results in resonance as shown in of AuNPs gives clear evidence over their therapeutic potential in the
Fig. 4. The light in resonance with surface plasmon leads the d elec- treatment of diseases like chronic inammation, pathological neo-
tron of gold NPs to oscillate. This is called as the surface plasmon res- vascularization, rheumatoid arthritis, and neoplastic disorders [77]. The
onance, since it occurs only at the surface. Jain et al. [69] reported that role of gold NPs invading the treatment for various inammatory dis-
the ratio of scattering to absorption was totally dependent on particle eases and other relative disorders that are context dependent, in orienta-
diameter. The ratio of scattering to absorption will increase as the tion with the evidences towards the anti-oxidative effect of traditional
particle size increases (20 to 80 nm). It was found that the deep red gold in treatment of diseases, has afrmed the urge for the need of
color of a 20 nm gold NP possesses a strong visible extinction band study over restorative effect of gold NPs.
at 520 nm, which will undergo a bathochromic shift (change in spec-
tral band position to longer wavelength) if the particle size is 4.3. Gold NPs for molecular imaging in cancer therapy and other related
increased. diseases
Optical behavior of gold NPs can be adjusted to near IR region by
synthesizing gold nanoshells as reported by Stober et al. [70]. The NPs like gold proved to have a unique approach in biomedical imag-
same phenomenon was reported for nanorods also. Nanorods were ing technique. Because of their small particle size, NPs can be a better
found to have two Plasmon resonances; the rst one is the transverse candidate to target the intracellular level in cells and thus can be
oscillation of electrons at 520 nm and the second one is the longitudi- monitored and visualized with the help of latest emerging imaging tech-
nal plasmon resonance which occurs at longer wavelengths [7174]. niques. Due to diversity in surface chemistry, unique physical proper-
ties, adaptable absorption and emission properties, exibility in
4.2. Multifunctional behavior of gold NPs for biomedical therapy synthesis and moreover surface modication clearly favor their poten-
tial as a probe unit for early detection of life threatening diseases like
Basically our body consists of various intracellular organelles cancer. It was reported that NPs were able to passively target tumor
which are found to be similar in size to that of NPs. Thus NPs offer cell with enhanced permeability and retention effect. Surface modica-
an advantage to the researcher to use nanotechnology to discover in- tion or functionalized gold NPs for biological and biomedical applica-
tracellular facts. NPs due to their small size can easily penetrate to the tions include bio-imaging, single molecule tracking, biosensing, drug
intracellular cell wall and if monitored they can give a plenty of useful delivery, transfection, and diagnostic. For example, through proper
information which can lead researchers in targeting of drugs or genes functionalization, the particles can be engineered to accumulate prefer-
and detection as well as for the treatment of diseases [74,75]. Gold entially in tumor cells using targeting ligands, providing a tool for cancer
NPs due to their unique properties were utilized by the scientic diagnosis and gene therapy [83,84].
community for both imaging and therapeutic applications in various Lymphatic system is also targeted by NPs through molecular sieving.
life threatening diseases. In order to obtain high specicity and accuracy to target tumor cells NPs
Soklov et al. [76] have investigated the multifunctional behavior of can be conjugated with tumor targeting ligands like peptides, small or-
gold NPs. He conjugated gold NPs with an antibody to bind to epider- ganic molecules and antibodies which help them specically target the
mal growth factor receptors (EGFRs) which are found to be overly tumor tissues or cells thus giving an early detection [8587]. Latest
expressed in cervical cancer cells. As gold NPs possess SPR scattering technology in the biomedical eld proposed the ability to trace the inor-
behavior and hence, these NPs can be useful for detection of cervical ganic NPs in the body even if they are present at intracellular level. Mo-
cancer cells with the help of the laser scanning confocal reectance lecular imaging technique helps the researchers for easy monitoring
[7783]. and visualization of inorganic NPs. This technique when applied can
Evaldas et al. [84] have studied on biodistribution of gold give necessary information regarding the cellular function, and charac-
nanoparticles ranging 2, 40 and 100 nm in the mouse lung following terization of molecular processes that took place even at molecular level
intratracheal instillation. Administered gold NPs were traced by without disturbing the cell integrity. NP systems like polymeric
autometallography (AMG) at both ultrastructural and light micro- nanoparticles, solid lipid nanoparticles, liposomes, nanotubes, metallic
scopic levels as shown in Fig. 5. Liver is the target site where NPs gen- nanoparticles, quantum dots and dendrimers are under investigation
erally to be deposited. Gold content was quantitatively determined by for molecular imaging and many studies have been done but inorganic
inductively coupled plasma mass spectrometry (ICP-MS) and by neu- NPs offer researchers many advantages over these NPs as a contrast
tron activation analysis (NAA). Their studies revealed that after an agent. Gold NPs possess a unique property of absorption and scattering
Fig. 4. Origin of surface plasmon resonance (SPR) due to interaction of the electrons.
dx.doi.org/10.1016/j.cis.2013.06.003
Fig. 5. Light and electron micrographs showing AMG enhanced gold nanoparticles in the lungs of mice following intratracheal instillations. A and B represent LM section taken from
the animals exposed to multiple intratracheal instillations with gold, 40 nm and 100 nm nanoparticles, respectively. AMG enhanced gold nanoparticles are located inside the lung
macrophages resembling cells. C represents a control, void of AMG staining. D and E are EM picture representing the animals exposed to multiple instillations with 40 nm gold
nanoparticles. Gold is located inside the lysosome/endosome-like vesicles. Scale bars: 20 m in AC; 1 m in D; and 500 nm in E.
Figure reproduced with permission from Ref. [84].
with a low toxicity prole thus making them a key gizmo in the eld of visualization of various diseases inside. Whole image will be differenti-
molecular imaging. Among all, gold NPs are widely used for biomedical ated with respect to contrast in the scan which arises from different fall-
imaging in medical eld. Due to low toxicity prole, biocompatibility ing of X-rays on the body parts. However, medical scientist claims a risk
with a high absorption coefcient makes gold NPs an efcient tool for of cancer due to frequent exposure to X-rays, but still CT scan provides
biomedical imaging. immense information about the body diseases and help to detect and
cure them at an early stage [91].
4.4. Role of gold NPs in deep tissue imaging Positron emission tomography (PET) is a nuclear imaging tech-
nique, which produces a 3 dimensional image of functional process
For deep tissue imaging basically two techniques came into exis- in the body by detection of gamma rays which were emitted from a
tence. One is magnetic resonance imaging (MRI) and the other is positron-emitting radiotracer (contrast agent) which will be further
computed tomography (CT) imaging. MRI [88] is used to study the displayed on computer after processing [92]. Versatile nature of
structure and function taking place in the whole body. As reported gold NPs has enabled the researchers to make use of them for optical
MR imaging detects the relaxation time (T) of water with respect to imaging of cells [9395] and phantoms [96,97] as shown in Fig. 6 [94].
a radio frequency range (RF). It gives a clear picture of different soft Many studies had been reported in imaging of gold NPs by dark-eld
tissues present in the body. MRI technique is currently one of the [98,99], photothermal interference contrast [100], atomic force mi-
most emerging, efcient and most widely used tools of all medical croscopy (AFM) [95], as well as uorescence and scanning electron
imaging techniques available [89]. MRI is usually associated with de- microscopy (SEM) [101].
tection of water protons in tissues, and as water is abundant. The pro- Gobin et al. [102] designed nanoshells for diagnostic imaging and
ton that exists is secondary to tritium in sensitivity, this limits the use at higher light intensity using optical coherence tomography. It was
of MRI in some cases [90]. reported that there was an enhancement of optical contrast in a
Computed tomography is one of the latest imaging techniques uti- mouse colon tumor model when gold nanoshells were injected. Kah
lized by scientist. It gives a three dimensional image and can easily et al. [103] carried out in vivo studies in order to measure the optical
scan the whole body of human being and can detect and make contrast of gold nanoshells in a mouse tumor model using the optical
dx.doi.org/10.1016/j.cis.2013.06.003
Fig. 6. Gold nanoparticles have been investigated for cell and phantom imaging using various techniques.
Reproduced with permission from Ref. [94].
coherence tomography (OCT). Gold nanoshells were administered 60 nm) were found to be stable in physiological conditions and are
into mice and particle surface parameters with respect to its concen- nontoxic and shows high clarity and intense X-ray images than the
tration in tumor is determined. It was concluded that a higher con- commercially available iodinated-contrast agent, omnipaque.
centration (1.5 1011 nanoshells/mL) of gold nanoshells in tumor Kattumuri et al. [109] prepared gold NPs stabilized with nontoxic
can only enhance the optical scattering intensity (OCT) signal near phytochemical gum-arabic matrix (GA-AuNPs) and assessed their
the tissue surface. Finally it was reported that an appropriate dose organ-specic localization after administration to pigs and studied
of gold nanoshells (6.2 109 particles/mL in tumor) achieves a their potential applicability as an X-ray contrast agent for molecular
good OCT signal enhancement. imaging. They concluded that GA-AuNPs can be used as nontoxic phy-
Kim et al. [104] prepared PEGylated gold nanoparticles (87 nm in tochemical tool in the production of readily administrable biocompat-
diameter) in aqueous dissolvable microneedles for controlled drug ible AuNPs for diagnostic and therapeutic applications.
delivery into hamster oral tissue in vivo. Results showed that there Excellent work was carried out by Boote et al. [110] by demon-
was an increase in average OCT (contrast level) in dysplastic and nor- strating gold NPs as a contrast agent by X-ray computed tomography
mal tissues by 33 to 20% respectively and oral cancer can be detected system using juvenile swine. Swine were injected gum arabic stabi-
at an early stage by OCT signals of gold NPs. lized gold nanoparticles (GA-AuNPs) and after that CT scan was
Park et al. [105] had reported that nanoshells grow brightly when done. Results reveal that the average uptake of GA-AuNP was
excited by near-infrared light. Comparative studies done by custom 380 g/g at the liver and 680 g/g at the spleen. This study clearly in-
built NIR laser scanning multi-photon microscope show that nanoshells dicated that gold NPs proved to be useful to enhance the visualization
were brighter than nanorods and 140 times brighter than nanobeads. of tissues using tomography system.
This study clearly indicates that the potential application of photon Kim et al. [111] had prepared gold NPs coated with polyethylene
induced photoluminescence signal for biological imaging. Li et al. glycol (PEG) to impart antibiofouling properties, which extends their
[106] had prepared gold NPs conjugated with transferrin molecules lifetime in the blood stream. Study was aimed to demonstrate the ad-
for effective targeting, imaging and therapy of breast cancer cells. vantages of gold NPs as a contrast agent compared to iodine-based com-
Cellular uptake was quantied by measuring the uorescence in- pounds which show several limitations like short imaging times due to
tensity. It was shown that gold NPs show excellent uorescence rapid renal clearance, renal toxicity, and vascular permeation. The re-
and the uptake of modied NPs with conjugated transferrin was clearly sults of the X-ray absorption coefcient in vitro show that there is a
visualized. 57 fold increase in the X-ray absorption behavior of gold NPs as com-
Ju H et al. [107] reported that laser generation of vapor bubbles pared to Ultravist, an iodine based compound. Additionally PEG coated
around plasmonic nanoparticles can be enhanced through the appli- gold NPs show much longer blood circulation time (N 4 h) than Ultravist
cation of an ultrasound eld by a technique called as photoacoustic (b 10 min). Scan images showed that PEG-coated AuNPs showed a clear
cavitation (PC). PC was investigated for a broad range of ultrasound delineation of cardiac ventricles. It was concluded that PEG coated gold
pressures and nanoparticle concentrations for gold nanorods and NPs into the hepatome bearing rats show high contrast images (approx-
nanospheres. Result studies reported that PC can potentially be pro- imately 2-fold) than the normal liver tissue. These results collectively
duced at depth in biological tissue without exceeding the safety limits proved that gold NPs can be a promising adjuvant as a CT contrast
for ultrasound or laser radiation at the tissue surface. agent for a blood pool and hepatoma imaging.
Chenjie et al. [108] reported the size effect of AuNPs on X-ray atten- Tobi et al. [112] have studied the feasibility of cancer diagnosis by
uation measured by CT. This investigation revealed that gold NPs (4 to injecting an anti-epidermal growth factor receptor conjugated gold
dx.doi.org/10.1016/j.cis.2013.06.003
nanoparticles (30 nm) into mice with previously xed human squa- the modern laser spectroscopy with the optical properties of metals
mous cell carcinoma head and neck cancer. It was found that even a which provide essential structural and surface interface information of
small undetectable tumor can be easily visualized with molecularly- single molecules [126]. Gold NPs due to their optoactive properties
targeted gold nanoparticles which are more suitable for active targeting were excellent substrate for SERS. Researchers have been exploring
than passive targeting. These types of studies can facilitate early cancer gold in Raman spectroscopy and surface enhanced Raman scattering
detection and measures can be taken to prevent them. (SERS) for imaging of cancer cells.
Popovtzer et al. [113] demonstrated the use of gold nanoprobes that Qian et al. [127] explained the biocompatibility and nontoxicity of
will selectively target tumor selective antigens (to detect head and neck gold NPs for in vivo tumor targeting and their detection based on
cancer in vitro) while inducing distinct contrast in CT imaging. It was PEGylated gold NPs and surface-enhanced Raman scattering (SERS).
found that attenuation coefcient for the molecularly targeted tumor From the results they revealed that the gold NPs proved to be safe to
cells is over 5 times higher than the untargeted and normal cells. This treat rheumatoid arthritis and has been found to amplify the Raman
study proves to be a key stone which can lead to early detection of can- scattering by 1415 orders of magnitude. PEGylated gold NPs were
cer with accurate and specic targeting of cancer cells that will impro- found to be considerably brighter than the semiconductor quantum
vise the existing cancer therapy. Gold nanorods were synthesized by dots. Xie et al. [128] synthesized ower like gold NPs (three-
the method of Nikoobakht and El-Sayed [114] using seed mediated dimensional branched nanoparticles with more than 10 tips) with
synthesis. high yield. Size can be easily varied or adjusted by controlling the reac-
Chi et al. [115] investigated different contrast agents with gold tion mixture. Results of the study showed that gold nanoowers exhibit
NPs for the detection of cancer related angiogenesis by synchrotron strong surface enhanced affects which can be used for efcient, stable
microradiology, microtomography and high resolution X-ray micros- and nontoxic Raman-active tag for in vivo applications.
copy. Results revealed that pristine gold NPs in combination with Jianqiang et al. [129] prepared starch-capped gold NPs with hexagon
heparin injection provided sufcient contrast to allow in vivo detec- and boot shapes using a nontoxic and biologically benign aqueous-
tion of small capillary species with 37 times higher density than phase synthetic route. It was found that the shape affects the SERS prop-
other nanoparticles. erties of gold NPs. It was found that boot-shaped nanoparticles can
Shukla and coworkers [116] investigated on the gold nanoparticles induce 100-fold SERS enhancements in sensitivity as compared with
which are considered nontoxic and can be traced histochemically by gold nanospheres. Finally with these enhanced SERS properties boot-
atomic force microscopy (AFM), even ultrastructurally. Such gold shaped nanoparticles can be used as a tool in biolabeling, bioassay,
nanoparticles are already in use for diagnostics and pharmaceutical ther- biodiagnosis, and even clinical diagnosis and therapy.
apy [117121]. Their study supports that only small amounts of gold Ramachandra et al. [130] emphasized the use of gold NPs based
nanoparticles are translocated from the lungs. However, Semmler- surface-enhanced Raman scattering (SERS) to differentiate the mouse
Behnke reported signicant translocation of smaller (1.4 nm) gold embryonic stem (mES) cells, undifferentiated single cells, embryoid
nanoparticles to the liver (0.7%) [122]. Similarly, they found that translo- bodies (EBs) and terminally differentiated cardiomyocytes. The results
cation of 2 nm particles takes place (only 1.31.9%). Takenaka et al. of this study revealed that gold NPs were successfully delivered into
treated rats with an aerosol of gold nanoparticles, 58 nm in diameter, all cell differentiation stages without affecting cell integrity or cell pro-
produced by a spark generator [123]. They observed accumulation of liferation. Transmission electron microscopy (TEM) studies conrmed
such particles in the pulmonary macrophages and epithelial cells with the localization of gold NPs inside the mitochondria, secondary lyso-
a low degree of systemic translocation. some, and endoplasmic reticulum. Using bright- and dark-eld imaging,
Bhatnagar et al. [124] had conjugated gold NPs with Copper 64 the bright scattering of gold NPs and nanoaggregates in all 3 ES cell dif-
using the macrocyclic chelator (1,4,7,10-tetraazacyclododecane- ferentiation stages could be visualized.
1,4,7,10-tetraacetic acid, DOTA) and polyethyleneglycol (GNP-(64) Cristina et al. [131] explained the capability of Raman spectroscopy
Cu/PEG2000) in order to utilize it as a radiotracer for PET and used to separate the spectral ngerprints of 10 different types of SERS
it to image T cells. T cells were rst electroporated with DNA plasmids nanoparticles in a living mouse after subcutaneous injection. The results
from the Sleeping Beauty transposontransposase system to co- revealed that all ve types of SERS NPs were successfully identied and
express a chimeric antigen receptor (CAR) specic for CD19 and Fire- were spectrally separated. The obtained results demonstrated the high
y luciferase (ffLuc) was propagated on CD19(+) K562-derived arti- potential for multiplexed imaging in living subjects in which SERS
cial antigen presenting cells. probes can provide better detection of biomarkers associated with re-
Xiao et al. [125] developed and characterized multifunctional gold spective disease.
nanorod (GNR) using anticancer drugs doxorubicin to target tumor Keren et al. [132] demonstrate the use of Raman spectroscopy in
cell and imaging by PET. Doxorubicin was covalently conjugated onto noninvasive deep-tissue molecular images in a living subject includ-
PEGylated GNR nanocarriers via a hydrazone bond to achieve ing in vivo tumor targeting. It was reported that Raman spectroscopy
pH-sensitive controlled drug release which can minimize non-specic offers great potential as a strategy tool for biomedical imaging of liv-
systemic spread of doxorubicin during circulation while maximizing ing subjects. As already discussed in the above review, advances in
the efciency of tumor-targeted anticancer drug delivery. It was found nanotechnology lead to more efcient targeted drug delivery of nu-
that the cRGD-conjugated GNR nanocarriers showed a higher cellular merous drugs. When it comes to cancer treatment therapy, NPs can
uptake. It was concluded that the unique optical properties of be a promising tool because of its small size that will make NPs easily
GNRs offer the possibility of using these multifunctional GNR-based perfuse through tumor cells and will retain more time leading to bet-
nanoplatform for combined cancer therapies (chemotherapy and ter accumulation of drug [133,134]. Overall NPs prove to be promis-
photothermal therapy) and multimodality imaging (PET, optical, ing in cancer treatment therapy irrespective of chemotherapy and
X-ray computed tomography). other techniques to treat cancer which face many limitations like
damage of healthy tissues and dose limiting side effects. Recently
4.5. Surface enhanced Raman scattering (SERS) many NP based therapeutics hit the market, whereas many were
under clinical trials or under preclinical development. A good exam-
Surface enhanced Raman spectroscopy or surface enhanced Raman ple of NP based therapeutics to treat cancer is Doxil (liposomal for-
scattering (SERS) is a surface-sensitive technique that enhances Raman mulation of doxorubicin) [135] and Abraxane (paclitaxel-bound
scattering by molecules adsorbed on metal surfaces and foremost ob- protein particle) [136] which are widely used for treatment of cancer.
served for analytes like gold (Au), silver (Ag) and copper (Cu) or alkali Gold NP based cancer therapy basically uses photothermal treat-
metals like lithium (Li), sodium (Na) and potassium (K). SERS combines ment (hyperthermia) to destroy cancer cells or tumors. Hyperthermia
dx.doi.org/10.1016/j.cis.2013.06.003
is dened as the application of heat to kill or destroy the tumor cells Patra et al. [157] developed a delivery system containing gold NPs
by maintaining a temperature above 40 C but a temperature above using cetuximab as a targeting agent, and gemcitabine as an antican-
42 C will cause serious problems like necrosis of cells, and denatur- cer drug and studied it's in vitro application against three pancreatic
ing of enzymes, and may cause functional changes to DNA and lastly cancer cell lines (PANC-1, AsPC-1 and MIA Paca2). The results re-
there is a high chance of rupturing of cell membrane leading to the revealed that the above system exhibits signicant inhibition of pancre-
lease of cellular content causing death [137142]. atic cell proliferation engrossed with cancer. It was concluded that
Cancer treatment using AuNPs is extensively studied by many re- gold NPs in combination with other agents can be used as a promising
searchers [143147]. It was reported that when gold NPs were irradiated approach to treat variety of cancers.
with laser pulses of specied wavelengths targeted nanoparticulate sys- Jiang et al. [158] produced gold and silver NPs coated with anti-
tems like gold nanospheres, nanorods, nanoshells, and nanocages can bodies that can regulate the process of membrane receptor internali-
kill bacteria and cancer cells [148]. zation. It was found that the binding and activation of membrane
Cobley et al. [149] described the gold nanocages, and plasmonic receptors and subsequent protein expression strongly depend on
nanoparticles, for the treatment of cancer due to their ability to con- the nanoparticle size. The obtained results revealed that NP size
vert light into heat effectively for photothermal treatment. Gold NPs range from 40 to 50 nm showed a profound effect. These results col-
had provided a new way to treat cancer with minimal side effects. lectively showed that gold NPs can be a useful core material to pro-
Au et al. [150] had prepared gold nanocages (65 7 nm average mote biological effects.
edge length and 7.5 1 nm diameter) by galvanic replacement reac- Huo et al. [159] have developed a facile nanoparticle immunoas-
tion using silver nanocubes. Further strong absorption peak at say for serum protein biomarker detection and analysis using gold
800 nm was conjugated with monoclonal antibodies (anti-HER2) in nanoparticles coupled by dynamic light scattering. Using the above
order to target breast cancer cells (SK-BR-3). Photothermal effect assay on both mice and human blood serum samples they discovered
was quantied by ow cytometry. The results clearly revealed that multiple molecular aberrations associated with prostate cancer. This
cells that had been targeted by gold immune cages respond promptly study revealed that there is a difference in protein corona and
to laser irradiation. Average number of cell was directly proportional mouse IgG level between different mice groups (i.e., mice with ag-
to the duration of exposure of cells to laser radiation which nally got gressive or less aggressive prostate cancer, and normal healthy con-
steady at 5 min. Thus proper combination of exposure time and opti- trols). It was found that the level of vascular endothelial growth
mal dosage of gold nanocages can effectively target tumor cells aiding factor (VEGF, a protein that is mainly associated with tumor angio-
for cancer treatment. genesis) is decreased in cancer samples. Thus this method proves to
Neal et al. [151] studied the feasibility of nanoshell-assisted be successful in utilizing biomarkers for prostate cancer and can be
photo-thermal therapy (NAPT) as they possess strong near infrared used to analyze serum protein. Recently, Fujita et al. investigated on
(NIR) absorption and by their optical absorptivities which can be the time-resolved acquisition of the SERS spectra and also allowed
modulated according to the need they can go through passive extrav- observation of the transport of AuNPs via a living cell [160]. Further-
asation because of their small size. Photothermal therapy was given more, researchers can use it in order to develop new biomarkers asso-
by a diode laser. It was found that after treatment all tumors were ciated with cancer and other human diseases.
abated and mice appeared to be healthy and tumor free. Study nally
concludes that this simple, noninvasive procedure shows great po-
tential for selective photo-thermal tumor ablation. 5. Radioactive isotopes of gold
Zharov et al. [152] had developed nanoclusters that enhance
photothermolysis of tumor through laser activation. It was reported Currently radioactive isotopes have been widely used for medical
that an increase in cell killing was observed. However, a target cell an- treatment such as cancer therapy with continually growing interest.
tigen was used in the study to give specicity to nanoclusters to make Diagaradjane et al. [161] investigated the gold nanoshells for
cancer cell sensitive to laser which will make this therapy more noninvasive modulation of in vivo tumor radiation response. A re-
effective. duction in hypoxic fraction of tumors was found which was noninva-
Letfullin et al. [153] studied gold nanoclusters that will be sively quantied by magnetic resonance temperature imaging.
transported to the target cancer cells either through physical trans- An increase in radiation dose induces vascular disruption with exten-
portation or through conjugating with antibodies or virus. After sive tumor necrosis. This study indicates that a novel integrated
reaching the target site, these gold nanoclusters will be irradiated antihypoxic and localized vascular disrupting therapy which can be
with short laser pulses of sufcient energy that will make these combined with other antitumor therapies for better cancer treatment
nanoclusters to explode. As concluded the explosion of these particles therapy.
may be accompanied by optical plasma, shock wave generation and Recent literature reported the use of gold (Au 198 colloid) for the
particle fragmentation, which collectively aid in killing of cells. treatment of pleural and peritoneal effusions due to neoplastic inl-
Zharov et al. [154] have investigated on gold nanoclusters conju- tration which was considered as an effective therapy as recurring ef-
gated with specic antibodies (anti-protein A antibodies) and laser fusions necessitate repeated aspirations [162164]. In other approach
was subjected upon them which makes the particle explodes, killing small gold grains had been employed for the treatment of carcinoma
targeted bacteria (Gram-positive bacterium Staphylococcus aureus). of the pancreas and to treat wide variety of tumors throughout the
This approach provides a real time achievement in the therapeutic body. It was reported that radioactive isotopes of short half-life can
area. Strong laser induced over heating effects accompanied by the be easily employed for permanent implants and radioactive isotopes
bubble formation around the gold NPs are the main reason for bacte- of longer half-life can be used for temporary implants [165].
rial damage which are clearly visualized by photothermal imaging. Nripen et al. [166] have prepared gum arabic glycoprotein (GA)-
Stern et al. [155] have reported that 5000 gold nanoshells per functionalized gold NPs and investigated their biocompatibility and
prostate cancer cells can kill cancer cells. Patra et al. [156] clearly therapeutic applications in cancer. It was revealed that gold NPs
demonstrated the potential of gold NPs as a drug delivery adjuvant (1218 nm) can easily target the tumors and can penetrate into
for the treatment of pancreatic cancer. Gold NPs were covalently tumor cells. It was found that -emitting gold-198 (198Au) shows high
bounded to cetuximab, as an active targeting agent and gemcitabine afnity for severely compromised immunodecient (SCID) mice having
as a therapeutic molecule in the therapy. It was reported that gold human prostate tumor xenografts. A single dose administration of 198Au
NPs can be utilized effectively for targeted drug delivery in the pan- resulted in drastic regression and revealed effective therapeutic control
creatic cancer. on growth of prostate tumors over 30 days.
dx.doi.org/10.1016/j.cis.2013.06.003
6. Role of gold NPs in DNA plasmid studies nanocomposites by UV irradiation followed by the thermal treatment
of chitosan oligomer solutions doped by HAuCl4. It was reported that
DNA plasmid model is a simple system that helps scientists to un- the antioxidant activity of the gold nanoparticles with respect to hy-
derstand the effect of radiation induced damage and free radical ef- droxyl radicals considerably depends on the specic surface area of
fects on cells. Plasmid DNA is a double stranded extrachromosomal the NPs.
DNA that is normally present in bacteria. This system allows to assess Nie and co-workers [176] laid special emphasis on alpha-tocopherol
the sensitization measurement of gold NPs without biological inter- (vitamin E) as a starting material to synthesize new synthetic antioxi-
vention in cells and without DNA damage [167,168]. dants with improved properties. Because of its potent antioxidant func-
Carter et al. [169] have investigated the distribution of energy re- tion and important role in clinical treatment alpha-tocopherol can be a
lease from the gold NPs to determine the distance for sensitization to useful base for new antioxidant. The antioxidant-functionalized gold
occur. They performed a Monte Carlo calculation and laid some nd- nanoparticles, Au@Trolox, was rst synthesized by self-assembly of
ings for the phenomena to occur. Firstly by enhanced absorption of thiol ligands that has been derived from Trolox, a vitamin E analogue,
X-rays by gold NPs, secondly effective release of electrons with on gold NPs. (2,2-diphenyl-1-picrylhydrazyl). Results were positive
low energy and lastly deposition of energy in water (radicals and and it was concluded that the assembly of chromanol groups on gold
electrons). This study also revealed the theoretical based nanoscale NPs could efciently enhance the activity of the vitamin E-derived anti-
energy disposition distribution underlying the gold-based sensitiza- oxidant which can lead to the development of many synthetic antioxi-
tion mechanisms. dant that can be benecial in many aspects.
Another study reported by Boudaiffa et al. [170] had thrown some Yin et al. [177] have stated that [Gd@C82(OH)22]n (endohedral
light on the damage of DNA. They reported the measurements of the metallofullernol) NPs can be a useful scavenger for ROS as it reduce
formation of single, double and multiple strands that breaks in pure the generation of ROS to an extent by production phase II enzymes
plasmid DNA after exposing them to 1050 eV electrons. It was no- which are closely associated with destruction and metabolism of ROS
ticed that very low energies which directly cannot ionize DNA were species. Barath et al. [178] had studied the effect of biologically synthe-
responsible for DNA damage. They reported that damage of DNA oc- sized AuNPs on hyperglycemic conditions in streptozotocin induced di-
curs through a mechanism named as dissociative electron attachment abetic mice. It was found that gold NPs exhibited an excellent control
(DEA) where the electrons get attached to DNA after exposure to over the blood glucose level, lipids and serum biochemical proles in di-
electrons where they resonate and forms a transient molecular abetic mice that were nearly equal to control mice blood glucose level.
anion which nally leads to fragmentation. The plasmid model allows Histological studies (liver and pancreas) that had been done for the
measurement of sensitization without the biological interactions of four groups control, diabetic control, diabetic control treated and gold
AuNPs with cells and without the impact of DNA repair. treated clearly revealed that gold NPs help in recovering of organs to
Zheng and Sanche [171] have reported that there will be an en- normal histology by keeping a check on ROS generation and inhibition
hanced radiation damage upto a magnitude of (7.5 units) when two of lipid peroxidation as shown in Figs. 7 and 8. Results clearly showed
cisplatin molecules and one gold NP were bound to plasmid DNA. that gold NPs can be a promising candidate for antioxidant action, as
Butterworth et al. [172] have assessed the effect of size and scaveng- they inhibit the formation of ROS, scavenging free radicals, thus increas-
ing conditions on radio sensitization. They characterized cellular cyto- ing the anti-oxidant defense enzymes of the body and creating a
toxic range of cell lines to 1.9 nm gold NPs. It was found that gold NPs sustained control over hyperglycemic conditions that will prove to be
caused signicant levels of cell type specic cytotoxicity, apoptosis very benecial in diabetic treatment.
and increased oxidative stress. When used as dose modifying agents it
was found that dose enhancement factors varied between the cell 8. Gold nanoparticles as biosensors
lines, with the highest enhancement being 1.9 in AGO-1522B cells at a
nanoparticle concentration of 100 g/mL. From the results it was no- Nanotechnology plays a key role in the development of biosen-
ticed that 1.9 nm gold NPs lead to cell line response like a decrease in sors. The run is on continuously improving biosensor sensitivity and
clonogenic survival rate, increased apoptosis and DNA damage which performance by using suitable nanomaterials for the fabrication
might be induced as the results of production of reactive oxygen which allows induction of many new signal transduction technolo-
species. This study lled a loophole for extensive and in-depth charac- gies in biosensors. Because of their small size nanosensors proved to
terization of gold NPs when measuring dose enhancing potential in can- be a promising tool for simple and rapid analyses in vivo. Inorganic
cer therapy which will be highly useful for the researchers of plasmid nanoparticles bound with biological moieties (protein and peptides)
DNA damage study. have been developed in order to detect and amplify signals.
Conde et al. [173] have developed a gold NP based approach for Maxwell et al. [179] have utilized colloidal gold nanocrystals to de-
molecular recognition and quantication of the BCRABL fusion tran- velop nanobiosensors that are able to recognize and detect specic
script (mRNA), which is responsible for chronic myeloid leukemia DNA sequences and single-base mutations. 2.5 nm gold NPs in the core
(CML). It was reported that the above method is the rst of its kind of biosensor function as both a nano-scaffold and a nano-quencher is at-
that is used for time quantication of a specic mRNA directly in can- tached with oligonucleotide molecules labeled with a thiol group at one
cer cells and is inexpensive and easy to use. Coming to sensitivity, it end and a uorophore at the other. However, the binding of core mole-
was found that the developed gold nanoprobes allow differential cule results in conformational change and this restored the uorescence
gene expression from 10 ng/L of total RNA and take less than of the quenched uorophore. They reported that the biosensor devel-
30 min to complete after total RNA extraction, minimizing RNA deg- oped was efciently able to detect single-base mutations in a homoge-
radation thus making it an excellent tool for early diagnosis of CML. neous format. Cai et al. [180] investigated the use of colloidal gold to
The DNA plasmid studies can yield useful information about the enhance the DNA immobilization on a gold electrode and to ultimately
mechanisms by which sensitization can occur and guide the design lower the detection limit of our electrochemical DNA biosensor. Colloidal
of in vitro and in vivo experiments. gold of 16 nm diameter was assembled onto a cysteamine modied gold
electrode which eases the attachment of an oligonucleotide with a
7. Gold nanoparticles as an antioxidant mercaptohexyl group at the 5-phosphate end, and therefore an in-
creased capacity for nucleic acid detection. They showed that the surface
It was reported that oxidative stress and reactive oxygen species densities of oligonucleotides on the Au colloid modied gold electrode
(ROS) were found to be crucial in a variety of diseases such as diabetes, were approximately (14) 1014 molecules cm2. It was concluded
cancer etc [174]. Yakimovich et al. [175] synthesized gold containing that Au nanoparticle lms on the Au electrode provide a novel
dx.doi.org/10.1016/j.cis.2013.06.003
Fig. 7. Protective effect of gold nanoparticles over hyperglycemia induced liver damage in diabetic mice. Histological specimens of mice liver after treatment of gold nanoparticles.
A. Control liver showing normal hepatic architecture, portal triad and central vein, B. diabetic control liver showing ground glass nuclei, lymphocytic inltrations along with lobular
inammation and high fatty cells, C. diabetic treated liver showing a signicant reduction in the fatty cells near to normal along with a clear central vein and D. gold treated liver for
45 days showing whole nuclei with central vein without any signicant morphological disruptions.
Fig. 8. Protective effect of gold nanoparticles over hyperglycemia induced damage in pancreas of diabetic mice. Histological sections of pancreas of experimental group of mice after
treatment with gold nanoparticles. A. Normal islets with clusters of purple stained -cells, B. the greater atrophy of -cells and vascular degeneration, C. increased size of -cells and
clear islets near to normal and D. normal atrophy of pancreatic cells similar to normal without any degenerative effects.
dx.doi.org/10.1016/j.cis.2013.06.003
Fig. 9. Schematic representation of PEG coated gold nanoparticles.
means for sequence-specic DNA (ssDNA) immobilization and ssDNA and proved that gold based electrochemical immunosensors enhance
detection. the electrochemical signal transduction of the binding event between
Glucose oxidase, horseradish peroxidase, xanthine oxidase, and antigen and antibody which in turns provide better surface for
carbonic anhydrase have been adsorbed to colloidal gold sols. It was immunoreagent stability upon immobilization [190]. A variety of
found that there is no change in enzymatic activity of xanthine oxi- small carcinogenic substances like, Aatoxin B1, [191], Ocra-toxin A,
dase after adsorption on colloidal gold as determined by active site [192], naphthalene [193], herbicides picloram [194] and hormones
titration with the stoichiometric inhibitor pterin aldehyde and by like human chorionic gonadotrophin have been detected by gold
measurement of the apparent Michaelis constant (K(M)). Further based electrochemical immunosensors.
these gold sols which previously adsorbed with glucose oxidase,
horseradish peroxidase, and xanthine oxidase are electrodeposited 9. Toxicity related aspects of gold nanoparticles
onto conducting matrices like platinum gauze and glassy carbon in
order to make enzyme electrodes which not only retain enzymatic ac- Gold in its bulk form has long been considered an inert, noble
tivity but also serve as a path to gave an electrochemical response to metal with some therapeutic and even medicinal value hence Au
the enzyme substrate in the presence of an appropriate electron NPs had been widely used in drug delivery, biomedical applications
transfer mediator [181]. like imaging and diagnosis of many diseases as it was found to be
Xu et al. [182] investigated the direct electrochemistry of horse- nontoxic, and biocompatible thus making it suitable for many of
radish peroxidase (HRP) that is immobilized on a colloidal gold mod- medical applications like wires in pacemakers, intravenous contrast
ied screen-printed carbon electrode (HRP-Au-SPCE). Immobilized agent for imaging and noninvasive detection of lung cancer [195].
HRP displayed a couple of stable and well-dened redox peaks with Much research had been done in this area which conrms the
a formal potential of 0.338 V and a heterogeneous electron transfer nontoxicity of gold NPs [196198]. However, on contrary some
rate constant of 0.75 0.04 s1. It showed a highly thermal stability, conicting researches are present which revealed the toxicity of
fast amperometric response and an electrocatalytic activity to the re- gold NPs. Yu et al. [199] had prepared water soluble gold NPs (0.8
duction of hydrogen peroxide (H2O2) without the aid of an electron to 15 nm) stabilized with triphenylphosphine derivatives and carried
mediator. Biosensor developed exhibited high sensitivity, good repro- out a cytotoxicity test in four cell lines that represent major functional
ducibility, and long-term stability for the determination of H2O2. cell types. It was found that cellular responses were size-dependent
Gold NPs serve as excellent uorescence quenchers for FRET- and revealed that 1.4 nm particles cause predominantly rapid cell
based assays due to its high molar extinction coefcients and broad death by necrosis within 12 h and 1.2 nm causes cell death by apo-
energy bandwidth [183184]. Precisely FRET based gold NPs prove ptosis. Dong et al. [200] investigated the irradiation effects on gold
to be an extraordinary bio-tool for sensing small organic molecules. NPs and cytotoxicity of gold NPs with human K562 cells using cell
Thiols at submicromolar levels have been detected by gold NPs Titre-Glo luminescent cell viability assay. Results revealed that
which are non-covalently attached to the nile red [185]. Tang et al. gold NPs show excellent radiation hardness and revealed a concen-
have developed a FRET based cholesterol sensor by using -cyclodex- tration dependent toxicity in cell lines. It was found that extremely
trin (-CD) functionalized AuNPs [186]. Nanocomposite gels of gold high concentration of gold NPs will cause a sharp decrease in K562
NPs/chitosan have been used for electrochemical monitoring of adhe- cell viability, whereas a low concentration of gold NPs showed no
sion, proliferation, and apoptosis of cells on the glassy carbon elec- inuence on the cell viability. Sung et al. [201] studied the toxicity of
trode (GCE) which showed an irreversible voltammetric response gold NPs in Sprague Dawley rats by inhalation. Study includes cellular
and enhanced the electron transmittance with a limit of detection of differential counts and cytotoxicity measurements, such as albumin,
8.71 102 cells/mL [187]. Electrocatalytic sensor to identify tumor lactate dehydrogenase (LDH), and total protein in cellular bronchoal-
cells specically has been developed by de la Escosura-Muniz. Anti- veolar lavage (BAL) uid. The obtained results revealed that there was
bodies conjugated with gold NPs were used to identify molecules on no statistical difference in cellular differential counts however, histo-
cell surface by catalytic hydrogen reduction [188]. Gold NPs conjugat- pathologic results showed minimal alveoli, an inammatory inltrate
ed with DNA have been used on GCEs using methylene blue (MB) as and increased macrophages in the rats which were highly dosed.
an electroactive label and differential pulse voltammetry (DPV) for DNA Abdelhalim and Jarrar [202] investigated the effect of gold NPs on
sensing. Results revealed that there was an enhanced signal response hepatic tissue by 50 or 100 ul of gold NP infusion of size (10, 20 and
during immobilization and hybridization [189]. It was investigated 50 nm for 3 or 7 days) on healthy male Wistar-Kyoto rats. It was
dx.doi.org/10.1016/j.cis.2013.06.003
Table 1
Various studies carried out using Gold NPs for biomedical applications.
Authors Preparation method Size Results Type of Year and

nanosystem reference
utilized
Zhang et al., 0.01% chloroauric acid (HAuCl44H2O) 13.5 nm Results conrmed that gold nanoparticles Nanospheres 2010, 191
solution is reuxed and 5 mL of 1% at low concentrations do not cause
sodium citrate solution added to the appreciable toxicity even after their
boiling solution. breakdown in vivo over time.
Gold NPs formed due to the reduction
of gold ions by citrate ions.
Zhang et al., 0.01% chloroauric acid (HAuCl44H2O) 5 to 60 nm Size-dependent in vivo toxicity study of Nanospheres 2011, 198
solution is reuxed and 5 mL of 1% PEG-coated gold NPs in mice was carried
sodium citrate solution added to the out which revealed that 5 nm and 10 nm
boiling solution. Gold NPs formed due particles mainly accumulate in the liver,
to the reduction of gold ions by citrate and that the 30 nm particles mainly
ions as shown in Fig. 9 accumulate in the spleen. Results revealed
that 10 and 60 nm PEG-coated gold NPs
are not safe whereas 5 and 30 nm particles
have relatively low toxicity.
Samim et al., Dioctyl sulfosuccinate sodium salt (AOT)/ 100 nm long Gold nanorods may be used to kill cancerous Nanorods 2011, 203
water/hexane reverse system by reduction with diameter cells in tumor in rat tissue when
of gold chloride with hydrazine hydrate. 20 nm subcutaneously injected.
Reuveni et al., Gold NPs were prepared using sodium 30 nm Results demonstrated that even a small Nanospheres 2011, 204
citrate with chloroauric acid tumor, that remain untraceable through
(HAuCl44H2O) solution anatomical computed tomography,
becomes clearly visible by the
molecularly-targeted gold nanoparticles
Puiyan Lee, Lipidic gold porphyrin nanoparticles 80 30 nm Incorporation of gold porphyrin into lipidic Nanospheres 2010, 205
were prepared using oil in water (o/w) nanoparticles resulted in a 16-fold increase
microemulsion technique in size of NPs.
Lipidic gold porphyrin NPs could decrease
systemic toxicity, as well as helps in
inhibiting tumor growth into the
neuroblastoma bearing mice.
Etame et al., Sodium citrate employed with sodium 424 nm It is reported that short PEG chain length Nanospheres 2011, 206
borohydride was used to generate (molecular weight 10002000) in
particles of less than 10 nm combination with smallest core size led to
optimum permeation in tumor vasculateure.
Juan Gu et al., Gold-doxorubicin nanoconjugates were 16.2 to 28.2 nm Gold nanoparticles can be successfully Nanoconjugate 2012, 207
developed by grafting doxorubicin (DOX) applied to overcome multiple drug resistance
onto polyethylene glycol (PEG)-modied (MDR) in cancer chemotherapy.
gold (Au) nanoparticles (Au-NPs) via
cleavable disulde (SS) linkage.
found that gold NPs had produced changes in hepatocytes, portal triads much more researches are still going on regarding gold as a therapeu-
and sinusoid integrity which may be due to accumulated residues tic candidate especially in the eld of cancer. The uniqueness of pro-
resulting from metabolic and structural disturbances caused by these viding combinational therapy made gold NPs a promising approach
gold NPs. Alterations are in terms of hydropic degeneration, cloudy in order to resolve cases of many life threatening diseases.
swelling, fatty degeneration, portal and lobular inltrate by chronic in-
ammatory cells and congestive dilated central veins as reported. Study
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CIS-01287; No of Pages 15

Advances in Colloid and Interface Science xxx (2013) xxxxxx

Contents lists available at SciVerse ScienceDirect

Advances in Colloid and Interface Science

Gold nanoparticles: A paradigm shift in biomedical applications

Fig. 1. Different types of gold NPs with their shapes.

Fig. 3. Schematic representation of preparation and conjugation of gold nanorods (RDG-GNRs).

Fig. 9. Schematic representation of PEG coated gold nanoparticles.

Authors Preparation method Size Results Type of Year and

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