Gold Nanoparticles - A Paradigm Shift in Biomedical Applications

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

journal homepage: www.elsevier.com/locate/cis
Gold nanoparticles: A paradigm shift in biomedical applications

Mohammed S. Khan a,, Gowda D. Vishakante a, Siddaramaiah H b
a
b
Dept. of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore 570015, India
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
Available online xxxx

Keywords:
Gold nanoparticles
Cancer therapy
Computed tomography
Biomedical applications
a b s t r a c t
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
imagination in order to utilize the nanotechnology in an innovative way according to their needs. One of the
major applications of nanotechnology is drug delivery through nanoparticles which is on boom for the researchers and gives a challenging environment for the researchers. Among them upcoming challenge is the
use of inorganic nanoparticles for the drug delivery and related aspects. There is growing interests in usage of inorganic 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.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
Gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . .
Synthesis of gold NPs . . . . . . . . . . . . . . . . . . . . .
3.1.
Gold nanospheres . . . . . . . . . . . . . . . . . . . .
3.2.
Gold nanorods . . . . . . . . . . . . . . . . . . . . .
3.3.
Gold nanoshells . . . . . . . . . . . . . . . . . . . . .
3.4.
Gold nanocages . . . . . . . . . . . . . . . . . . . . .
4.
Properties of gold Nps . . . . . . . . . . . . . . . . . . . . .
4.1.
Optical properties . . . . . . . . . . . . . . . . . . . .
4.2.
Multifunctional behavior of gold NPs for biomedical therapy
4.3.
Gold NPs for molecular imaging in cancer therapy and other
4.4.
Role of gold NPs in deep tissue imaging . . . . . . . . .
4.5.
Surface enhanced Raman scattering (SERS) . . . . . . . .
5.
Radioactive isotopes of gold . . . . . . . . . . . . . . . . . .
6.
Role of gold NPs in DNA plasmid studies . . . . . . . . . . . .
7.
Gold nanoparticles as an antioxidant . . . . . . . . . . . . . .
8.
Gold nanoparticles as biosensors . . . . . . . . . . . . . . . .
9.
Toxicity related aspects of gold nanoparticles . . . . . . . . . .
10.
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Nanotechnology can be dened as the design, evaluation, production and application of structures, devices and systems by controlling
Corresponding author at: Dept. of Pharmaceutics, JSS College of Pharmacy, JSS
University, Mysore 570015, Karnataka, India. Tel.: + 91 8088054966.
E-mail address: mshuaibkhan68@gmail.com (M.S. Khan).
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the size and shape at a nanometer scale [1]. As a forthcoming eld nanotechnology is about to bring fundamental changes in manufacturing
and will make a huge impact on every aspect of life sciences namely
drug delivery, diagnostics, neutraceuticals and production of biomaterials as well as on electronics. Developing newer molecules and manipulating those available naturally in nanosize could be appealing for their
greater potential to improve health care [2]. Several pharmacological
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
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

the last few years. Well dened knowledge of the fundamental relationships would allow nanoparticles (NPs) to be fabricated with denite
size and surface characteristics and/or modied for delivery to specic
cells or organs in the body. Over the past few decades, advances in
nanotechnology have spurred development in many biomedical applications including cancer therapy, drug delivery and as biomarkers in
imaging techniques. Many nanoparticle based drug delivery systems
have been designed in order to fulll the ever growing need of the science in both medical as well as in pharmaceutical elds. Latest technological advancements have brought many new innovative drug delivery
systems into commercialized forms. The most targeted area of contemporary research using nanoparticles especially focuses on targeted drug
delivery at intracellular level in order to combat life threatening diseases. Over the years, scientist has achieved better insights into gold
NP systems and is in continuous run in order to better establish the
use of gold NPs in all sectors of pharmaceutical therapy as a major
drug delivery approach.
This review focuses on the gold nanoparticles (AuNPs) that prove
to be an important tool for a number of biomedical applications like
drug delivery, imaging and treatment of major life threatening diseases. Functional metallic nanomaterials have gained much attention
from the researchers not only as a drug delivery vehicle or diagnostic
tracer tool but also as an optical carrier. Recently, gold has gained
much more attention and tremendous works have been done due to
its unique therapeutic activity, inert and nontoxic nature. In past
few years scientist had explored gold as a major drug delivery tool
which not only provides therapeutic benets but also acts as a tracer
for diagnostic imaging which will give structural information on
very molecular level. Various researchers had prepared gold particles
in different shapes and sizes for targeting many diseases. The use of
gold particles not only offers many advantages for the researchers
for biological actions but also provides a possibility of imaging a single particle deep inside the body tissue by various imaging techniques
which not only target specic cells (e.g.: tumor cells) but also open a
window for gene therapy. However, inspite of numerous works done
on gold particles, having exact control on intracellular delivery and
intracellular localization of NPs remains a major challenge and continuous research works are in progress in order to give a clear-cut information. In this review we focused on most latest biomedical
applications and clinical advances of gold nanoparticles. The applications of gold in cancer therapy, as a diagnostic and imaging tool, and
the role of gold in DNA model studies, as an antioxidant and as biosensors had been widely discussed.
2. Gold nanoparticles
Looking in the past, gold has been already reported as a health adjuvant. Chinese and Indian culture reported the use of gold compounds in the form of Swarna Bhasma for treatment of various
health needs like increasing vital power and curing male impotence
[35]. Its unique properties like inertness, nontoxic nature towards
cell and biocompatibility of gold make it useful and attractive materials for the researchers for biological and biomedical applications as
well as relevant in therapy and imaging [617].
Myocrism (sodium aurothiomalate) and Solganol (aurothioglucose) are water soluble gold complexes present which show
benecial effect in rheumatoid arthritis. Earlier in 1978 cisplatin
was approved by the Food and Drug administration (FDA) as an
antitumor agent. This nding opens a new gate for the researchers
to investigate and explore deeply, using gold NPs as an antitumor
agent. It was found that the combination of gold (I) and gold (III)
complexes enhanced the antitumor activity of known antitumor compound [18,19].
Gold NPs have the tendency to absorb and scatter visible and near
infrared (NIR) light resonantly upon excitation of surface plasmon
oscillation. Detection of biological events at the single molecule

level has been used for biosensing by exploiting the distancedependent scattering properties of the AuNPs. Upon getting excited
plasmon resonance band can be spectrally modied over a wide
range. The outcome is that the sense of light scattering signal is
more profound (highly intense) and comparatively much brighter
than the chemical uorophores. This property can be useful in imaging techniques i.e., single molecule imaging can be achieved [20,21].
Recently there has been an explosion in gold NP research, with a
rapid increase in gold NP publications in diverse elds including imaging, bioengineering and molecular biology. It is probable that this
relates to a similar increase in the broader eld of nanotechnology, increased governmental awareness and funding, and rapid progress in
chemical synthesis and molecular biology [22].
3. Synthesis of gold NPs
The synthesis or production of nanoparticles follows the same
fundamental rule i.e., reduction of size (top-down technique). Gold
NPs can be produced by reduction of gold salts in the presence of stabilizing agents in order to prevent agglomeration. The gold NPs can be
prepared in three different methods:
(i) Physical methods like microwave (MW) irradiation, sonochemical method, ultra violet (UV) radiation, laser ablation,
thermolytic process and photochemical process [2327].
(ii) Chemical methods employ the use of chemical reactions like
the generation of gold NPs in an aqueous medium using citrate
or sodium borohydride as a reducing agent. However, it is well
reported that if citrate concentration is well controlled small
and uniform size gold NPs can be produced [2830]. Melissa
synthesized gold NPs by reducing gold (IV) chloride (AuCl4)
and sliver nitrate (AgNO3) using heparin and hyaluronan, as
reducing and stabilizing agents respectively. Produced NPs
showed good stability under physiological conditions [31].
Most advantageous of gold NPs is that they can be easily functionalized or modied by tagging the thiol linkers in their
monolayers. The surface modication of AuNPs can be easily
carried out with peptides, proteins, oligosaccharides, and
nucleic acids [3138]. The use of an inorganic matrix as a support or host to produce the nanoparticles is another way to produce gold NPs. Mukherjee et al. had used silica supported
surface which contains a silanol group that helps to reduce
chloroaurate ion to gold NPs [39].
(iii) Another way to produce NPs is the supercritical uid technology. A supercritical uid can be generally dened as a solvent at
a temperature and pressure above its critical point, at which
the uid remains a single phase regardless of pressure [40]. Supercritical CO2 (SC CO2) is the most widely used supercritical
uid because of its mild critical conditions (Tc = 31.1 C,
Pc = 73.8 bars), non-toxicity, non-ammability, and low cost.
The most common processing techniques involving supercritical uids are supercritical anti-solvent (SAS) and rapid expansion of critical solution (RESS). The process of SAS employs a
liquid solvent, e.g., methanol, which is completely miscible
with the supercritical uid (SC CO2), to dissolve the solute to
the micronized; at the process conditions, because the solute
is insoluble in the supercritical uid, the extract of the liquid
solvent by supercritical uid leads to the instantaneous precipitation of the solute, resulting in the formation of NP. Thote and
Gupta reported the use of a modied SAS method for the formation of hydrophilic drug dexamethasone phosphate drug
NP for microencapsulation purpose [41]. Supercritical uid
technology also helps to prepare lanthanides such as europium
(Eu), yttrium (Y) and gadolinium (Gd), and transitional metal
based nanoparticles [42].
dx.doi.org/10.1016/j.cis.2013.06.003
Fig. 1. Different types of gold NPs with their shapes.
(iv) Biological methods are like the use of fungus or bacteria as a

source can be used to produce NPs [43,44]. Biological methods
to produce gold NPs have been used as an alternative in order
to avoid the use of organic solvents that have been used in
chemical and physical processes, thus making biological process an eco-friendly approach for the production of gold NPs.
Different types of gold NPs had been shown in Fig. 1.
3.1. Gold nanospheres
Gold nanospheres also referred as gold colloids and their size lie in
the range of 2 nm100 nm and can be synthesized by controlled reduction of an aqueous solution of HAuCl4 using a reducing agent
(ex: citrate). The particle size of gold NPs can be easily controlled
by varying gold to reducing agent ratio. It is well documented that
the small amount of citrate will yield large sized nanospheres [45], a
two phase method which can produce stable gold nanospheres,
with reduced dispersity and well-controlled size. Most of all these
reported the use of the NaBH4 as reduction of HAuCl4 in the presence
of any thiolated ligand (tetraoctylammonium bromide, TOAB)
[46,29]. This method was also optimized to produce nanospheres of
small size. Manipulating the thiol/gold ratio and a quicker addition
of a reducing agent in cold solution will produce gold nanospheres
of smaller size with good dispersity.
Leff et al. [47] have investigated on the amine-capped gold
nanocrystals with diameter of 2570 . All physical characterizations
that had been carried-out are consistent with a charge-neutral amine/
gold surface interaction described by a weak covalent bond. The
obtained data indicates that the stability of gold nanocrystals produced was stable and appears to be kinetic rather than thermodynamic, in nature.
Lauren et al. [48] synthesized gold NPs by reducing HAuCl4 with sodium citrate and found that the obtained NPs are stable and highly-pure
and were used as a probe to transport of cleavage-stage zebrash embryos in order to assess the effects on embryonic development. Yuan
et al. [49] documented the use of biocompatible block copolymers
(poly(2-methacryloyloxy) ethyl phosphorylcholine) (PMPC) block
and a poly(2-(dimethylamino) ethyl methacrylate) (PDMA) for the
synthesis of sterically stabilized gold nanospheres in an aqueous solution as shown in Fig. 2. This research study proved to be useful in the
adsorption of the PDMA block on the surface of gold nanoparticles

whereas PMPC functions as a stabilizing block, which ultimately results
in highly biocompatible gold sols in an aqueous solution without any
external reducing agent.
3.2. Gold nanorods
Gold nanorods have received much attention as a drug delivery
vehicle due to its low cytotoxicity, excellent stability, biocompatibility
and suitable physiochemical parameters. Numerous works had been
done using gold nanorods as a drug delivery adjuvant. As reported
by Martin et al. [50] and van der Zande et al., [51] gold nanorods
can be synthesized using a template based method i.e., electrochemical deposition of gold in pores of a polycarbonate or an alumina
based template membranes.
Xu et al. prepared gold nanorods using the seed-mediated templateassisted procedure by reducing gold salt in the presence of surfactantdirected synthesis and investigated the benet of combining RGDconjugated gold nanorods (RDG-GNRs) that target integrin with
irradiation in melanoma cancer cells and concluded that RGD-GNRs
could sensitize melanoma A375 cells to irradiation as shown in Fig. 3
[52,53]. Murphy and Jana [54] had reported the wet chemical synthesis
of monodisperse gold nanorods with high aspect ratio. The method involves the surfactant directed growth of nanorods from spherical seeds.
It was reported that gold nanorods of aspect ratios of 4.6 1.2, 13 2
and 18 2.5 have been developed using the above method. The only
disadvantage of this method is, gold nanorod yield was found to be
low as it was difcult to separate gold nanorods from other different
shaped gold side products that were formed in the reaction.
The length and diameter of nanorods have to be determined and it
is completely dependent on the pore diameter of template membrane
whereas length can be controlled by keeping a check on the amount
of gold deposited within the pores of template membrane. However,
a major limitation of production of gold nanorods is its yield. A low
yield is found since only one single monolayer nanorod is prepared.
Formation of gold nanorods through electrochemical routes has
been studied. Chang et al. [55] used an electrochemical method to prepare an aqueous solution containing gold nanorods. The effects of wavelength, laser uence and matrix content on the size, shape, purity and
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 ammonium salt stabilized clusters in a size range of 16 nm. This method
possesses advantages of high yield, easy isolation and simple control
of particle size of nanorods.
Several other methods had been employed to prepare nanorods of
desired size and shape. Canizal et al. [57] developed nanorods by
bioreduction methods. Sharma et al. [58] reported the use of centrifugation techniques for excellent separation of colloidal gold nanorods
from a mixture of nanorods and nanospheres. It is well reported in
that the hydrodynamic behavior of nanorods and nanoparticles behaves differently. It is concluded that shape-dependent drag causes
particles to have shape-dependent sedimentation behavior which
will give an ease of separation of nanorods.
Nidome et al. [59] had prepared nanorods for drug delivery applications. Plasmid DNA was rst absorbed onto PC-modied gold
nanorods by electrostatic interaction and from that release was tested
by illuminating the PCnanorodDNA solution with the fundamental
light of a Q-switched Nd:YAG laser. DNA release was conrmed by gel
electrophoresis.
3.3. Gold nanoshells

Nanoshell or generally called as nanoshell plasmon, is nothing but
another name given to nanoparticles which have a dielectric core
covered by thin metallic shell over it (more specically gold). These
nanoparticles engage a quasiparticle (emergent phenomena that take
place when solid behaves like weakly interacting particles in free
space) called plasmon which is a quantum of plasma oscillation where
electrons concurrently oscillate with respect to ions that are present
[60]. Gold nanoshells are spherical NPs with diameters ranging in size
from 10 to 200 nm. As novel nanostructures, they possess a remarkable
set of optical, chemical and physical properties, which make them ideal
candidates for enhancing cancer detection, cancer treatment, cellular
imaging and medical biosensing. They can be easily modied to
absorb/scatter light at specic wavelengths in the visible and nearinfrared (NIR) regions of the spectrum [47].
Oldenburg and coworkers [61] were rst to develop silica-core

gold nanoshells, a new frequency-agile nanoparticles. Basically a
four step synthesis procedure had been reported. The rst step aims
to develop monodisperse silica nanoparticles using the Stober method to produce the spherical dielectric cores. The second step indulges
the functionalization of silica nanoparticles by the adsorption of an
organosilane (3-aminopropyltriethoxysilane), with its amine tails
coming out from the surface. The third step is to coat the silica NPs
by a colloidal solution of gold (12 nm in diameter). Finally reduction
takes place to produce silica NPs covered with a uniform coat of gold
thus nally producing a gold nanoshell.
3.4. Gold nanocages
Gold nanocages are hollow porous gold NPs, size basically ranges in
between 10 and 150 nm and consists of hollow interiors and porous
walls. They are generally produced by silver nanoparticles with
chloroauric acid (HAuCl4) in boiling water. The nanocages are prepared
by simple galvanic replacement reaction which occurs between solutions containing metal precursor salts and Ag nanostructures. The
differences in electrochemical potential control the whole reaction ultimately depositing the reduced metal on the surface of gold nanostructure [62]. When it comes to the size of nanocages these can be easily
controlled by adjusting the molar ratio of silver to HAuCl4. Other features that make gold nanocages an exciting approach are their compact
sizes, large absorption cross sections, bio-inertness and ability for surface modication based on Au-thiolate chemistry [63].
4. Properties of gold Nps
4.1. Optical properties
Inorganic NPs offer researchers a exible approach to make use of
NPs according to their use and needs. Adjustment of optoelectronic
properties due to the shape and size of inorganic NPs makes them different from other NP systems and applicable for various biomedical
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

strong surface plasmon resonance (SPR) band that totally depends
on particle size, shape and dielectric strength of the metal and the
surrounding medium [6467,42]. Susia and El Sayed [68] explained
the phenomena of SPR clearly. Free electrons in the metal (d electrons) will travel through a mean path (mean free path 50 nm) thus
particle less than 50 nm will not get scattered from the bulk rather
the interaction will happen on the surface that will help in scattering.
Thus when the wavelength of light is larger than the particle size it
will switch over the charge and results in resonance as shown in
Fig. 4. The light in resonance with surface plasmon leads the d electron of gold NPs to oscillate. This is called as the surface plasmon resonance, since it occurs only at the surface. Jain et al. [69] reported that
the ratio of scattering to absorption was totally dependent on particle
diameter. The ratio of scattering to absorption will increase as the
particle size increases (20 to 80 nm). It was found that the deep red
color of a 20 nm gold NP possesses a strong visible extinction band
at 520 nm, which will undergo a bathochromic shift (change in spectral band position to longer wavelength) if the particle size is
increased.
Optical behavior of gold NPs can be adjusted to near IR region by
synthesizing gold nanoshells as reported by Stober et al. [70]. The
same phenomenon was reported for nanorods also. Nanorods were
found to have two Plasmon resonances; the rst one is the transverse
oscillation of electrons at 520 nm and the second one is the longitudinal plasmon resonance which occurs at longer wavelengths [7174].
4.2. Multifunctional behavior of gold NPs for biomedical therapy
Basically our body consists of various intracellular organelles
which are found to be similar in size to that of NPs. Thus NPs offer
an advantage to the researcher to use nanotechnology to discover intracellular facts. NPs due to their small size can easily penetrate to the
intracellular cell wall and if monitored they can give a plenty of useful
information which can lead researchers in targeting of drugs or genes
and detection as well as for the treatment of diseases [74,75]. Gold
NPs due to their unique properties were utilized by the scientic
community for both imaging and therapeutic applications in various
life threatening diseases.
Soklov et al. [76] have investigated the multifunctional behavior of
gold NPs. He conjugated gold NPs with an antibody to bind to epidermal growth factor receptors (EGFRs) which are found to be overly
expressed in cervical cancer cells. As gold NPs possess SPR scattering
behavior and hence, these NPs can be useful for detection of cervical
cancer cells with the help of the laser scanning confocal reectance
[7783].
Evaldas et al. [84] have studied on biodistribution of gold
nanoparticles ranging 2, 40 and 100 nm in the mouse lung following
intratracheal instillation. Administered gold NPs were traced by
autometallography (AMG) at both ultrastructural and light microscopic levels as shown in Fig. 5. Liver is the target site where NPs generally to be deposited. Gold content was quantitatively determined by
inductively coupled plasma mass spectrometry (ICP-MS) and by neutron activation analysis (NAA). Their studies revealed that after an
instillation period of 1 h only, gold NPs appeared in lung macrophages. It was found that only a tiny fraction of the gold NPs is
translocated in systemic circulation and translocation rate was
greatest with the 2 nm gold particles and they get accumulated in
the liver.
The promising potential of AuNPs in the treatment of inammatory
and autoimmune diseases has augmented greater interest to researchers
in order to evaluate the anti-oxidative and anti-hyperglycemic activity
of the gold nanoparticles in the diabetic patients. The inhibitory activity
of AuNPs gives clear evidence over their therapeutic potential in the
treatment of diseases like chronic inammation, pathological neovascularization, rheumatoid arthritis, and neoplastic disorders [77]. The
role of gold NPs invading the treatment for various inammatory diseases and other relative disorders that are context dependent, in orientation with the evidences towards the anti-oxidative effect of traditional
gold in treatment of diseases, has afrmed the urge for the need of
study over restorative effect of gold NPs.
4.3. Gold NPs for molecular imaging in cancer therapy and other related
diseases
NPs like gold proved to have a unique approach in biomedical imaging technique. Because of their small particle size, NPs can be a better
candidate to target the intracellular level in cells and thus can be
monitored and visualized with the help of latest emerging imaging techniques. Due to diversity in surface chemistry, unique physical properties, adaptable absorption and emission properties, exibility in
synthesis and moreover surface modication clearly favor their potential as a probe unit for early detection of life threatening diseases like
cancer. It was reported that NPs were able to passively target tumor
cell with enhanced permeability and retention effect. Surface modication or functionalized gold NPs for biological and biomedical applications include bio-imaging, single molecule tracking, biosensing, drug
delivery, transfection, and diagnostic. For example, through proper
functionalization, the particles can be engineered to accumulate preferentially in tumor cells using targeting ligands, providing a tool for cancer
diagnosis and gene therapy [83,84].
Lymphatic system is also targeted by NPs through molecular sieving.
In order to obtain high specicity and accuracy to target tumor cells NPs
can be conjugated with tumor targeting ligands like peptides, small organic molecules and antibodies which help them specically target the
tumor tissues or cells thus giving an early detection [8587]. Latest
technology in the biomedical eld proposed the ability to trace the inorganic NPs in the body even if they are present at intracellular level. Molecular imaging technique helps the researchers for easy monitoring
and visualization of inorganic NPs. This technique when applied can
give necessary information regarding the cellular function, and characterization of molecular processes that took place even at molecular level
without disturbing the cell integrity. NP systems like polymeric
nanoparticles, solid lipid nanoparticles, liposomes, nanotubes, metallic
nanoparticles, quantum dots and dendrimers are under investigation
for molecular imaging and many studies have been done but inorganic
NPs offer researchers many advantages over these NPs as a contrast
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
molecular imaging. Among all, gold NPs are widely used for biomedical
imaging in medical eld. Due to low toxicity prole, biocompatibility
with a high absorption coefcient makes gold NPs an efcient tool for
biomedical imaging.
4.4. Role of gold NPs in deep tissue imaging
For deep tissue imaging basically two techniques came into existence. One is magnetic resonance imaging (MRI) and the other is
computed tomography (CT) imaging. MRI [88] is used to study the
structure and function taking place in the whole body. As reported
MR imaging detects the relaxation time (T) of water with respect to
a radio frequency range (RF). It gives a clear picture of different soft
tissues present in the body. MRI technique is currently one of the
most emerging, efcient and most widely used tools of all medical
imaging techniques available [89]. MRI is usually associated with detection of water protons in tissues, and as water is abundant. The proton that exists is secondary to tritium in sensitivity, this limits the use
of MRI in some cases [90].
Computed tomography is one of the latest imaging techniques utilized by scientist. It gives a three dimensional image and can easily
scan the whole body of human being and can detect and make
visualization of various diseases inside. Whole image will be differentiated with respect to contrast in the scan which arises from different falling of X-rays on the body parts. However, medical scientist claims a risk
of cancer due to frequent exposure to X-rays, but still CT scan provides
immense information about the body diseases and help to detect and
cure them at an early stage [91].
Positron emission tomography (PET) is a nuclear imaging technique, which produces a 3 dimensional image of functional process
in the body by detection of gamma rays which were emitted from a
positron-emitting radiotracer (contrast agent) which will be further
displayed on computer after processing [92]. Versatile nature of
gold NPs has enabled the researchers to make use of them for optical
imaging of cells [9395] and phantoms [96,97] as shown in Fig. 6 [94].
Many studies had been reported in imaging of gold NPs by dark-eld
[98,99], photothermal interference contrast [100], atomic force microscopy (AFM) [95], as well as uorescence and scanning electron
microscopy (SEM) [101].
Gobin et al. [102] designed nanoshells for diagnostic imaging and
at higher light intensity using optical coherence tomography. It was
reported that there was an enhancement of optical contrast in a
mouse colon tumor model when gold nanoshells were injected. Kah
et al. [103] carried out in vivo studies in order to measure the optical
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

into mice and particle surface parameters with respect to its concentration in tumor is determined. It was concluded that a higher concentration (1.5 1011 nanoshells/mL) of gold nanoshells in tumor
can only enhance the optical scattering intensity (OCT) signal near
the tissue surface. Finally it was reported that an appropriate dose
of gold nanoshells (6.2 109 particles/mL in tumor) achieves a
good OCT signal enhancement.
Kim et al. [104] prepared PEGylated gold nanoparticles (87 nm in
diameter) in aqueous dissolvable microneedles for controlled drug
delivery into hamster oral tissue in vivo. Results showed that there
was an increase in average OCT (contrast level) in dysplastic and normal tissues by 33 to 20% respectively and oral cancer can be detected
at an early stage by OCT signals of gold NPs.
Park et al. [105] had reported that nanoshells grow brightly when
excited by near-infrared light. Comparative studies done by custom
built NIR laser scanning multi-photon microscope show that nanoshells
were brighter than nanorods and 140 times brighter than nanobeads.
This study clearly indicates that the potential application of photon
induced photoluminescence signal for biological imaging. Li et al.
[106] had prepared gold NPs conjugated with transferrin molecules
for effective targeting, imaging and therapy of breast cancer cells.
Cellular uptake was quantied by measuring the uorescence intensity. It was shown that gold NPs show excellent uorescence
and the uptake of modied NPs with conjugated transferrin was clearly
visualized.
Ju H et al. [107] reported that laser generation of vapor bubbles
around plasmonic nanoparticles can be enhanced through the application of an ultrasound eld by a technique called as photoacoustic
cavitation (PC). PC was investigated for a broad range of ultrasound
pressures and nanoparticle concentrations for gold nanorods and
nanospheres. Result studies reported that PC can potentially be produced at depth in biological tissue without exceeding the safety limits
for ultrasound or laser radiation at the tissue surface.
Chenjie et al. [108] reported the size effect of AuNPs on X-ray attenuation measured by CT. This investigation revealed that gold NPs (4 to
60 nm) were found to be stable in physiological conditions and are

nontoxic and shows high clarity and intense X-ray images than the
commercially available iodinated-contrast agent, omnipaque.
Kattumuri et al. [109] prepared gold NPs stabilized with nontoxic
phytochemical gum-arabic matrix (GA-AuNPs) and assessed their
organ-specic localization after administration to pigs and studied
their potential applicability as an X-ray contrast agent for molecular
imaging. They concluded that GA-AuNPs can be used as nontoxic phytochemical tool in the production of readily administrable biocompatible AuNPs for diagnostic and therapeutic applications.
Excellent work was carried out by Boote et al. [110] by demonstrating gold NPs as a contrast agent by X-ray computed tomography
system using juvenile swine. Swine were injected gum arabic stabilized gold nanoparticles (GA-AuNPs) and after that CT scan was
done. Results reveal that the average uptake of GA-AuNP was
380 g/g at the liver and 680 g/g at the spleen. This study clearly indicated that gold NPs proved to be useful to enhance the visualization
of tissues using tomography system.
Kim et al. [111] had prepared gold NPs coated with polyethylene
glycol (PEG) to impart antibiofouling properties, which extends their
lifetime in the blood stream. Study was aimed to demonstrate the advantages of gold NPs as a contrast agent compared to iodine-based compounds which show several limitations like short imaging times due to
rapid renal clearance, renal toxicity, and vascular permeation. The results of the X-ray absorption coefcient in vitro show that there is a
57 fold increase in the X-ray absorption behavior of gold NPs as compared to Ultravist, an iodine based compound. Additionally PEG coated
gold NPs show much longer blood circulation time (N 4 h) than Ultravist
(b 10 min). Scan images showed that PEG-coated AuNPs showed a clear
delineation of cardiac ventricles. It was concluded that PEG coated gold
NPs into the hepatome bearing rats show high contrast images (approximately 2-fold) than the normal liver tissue. These results collectively
proved that gold NPs can be a promising adjuvant as a CT contrast
agent for a blood pool and hepatoma imaging.
Tobi et al. [112] have studied the feasibility of cancer diagnosis by
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 squamous cell carcinoma head and neck cancer. It was found that even a
small undetectable tumor can be easily visualized with molecularlytargeted gold nanoparticles which are more suitable for active targeting
than passive targeting. These types of studies can facilitate early cancer
detection and measures can be taken to prevent them.
Popovtzer et al. [113] demonstrated the use of gold nanoprobes that
will selectively target tumor selective antigens (to detect head and neck
cancer in vitro) while inducing distinct contrast in CT imaging. It was
found that attenuation coefcient for the molecularly targeted tumor
cells is over 5 times higher than the untargeted and normal cells. This
study proves to be a key stone which can lead to early detection of cancer with accurate and specic targeting of cancer cells that will improvise the existing cancer therapy. Gold nanorods were synthesized by
the method of Nikoobakht and El-Sayed [114] using seed mediated
synthesis.
Chi et al. [115] investigated different contrast agents with gold
NPs for the detection of cancer related angiogenesis by synchrotron
microradiology, microtomography and high resolution X-ray microscopy. Results revealed that pristine gold NPs in combination with
heparin injection provided sufcient contrast to allow in vivo detection of small capillary species with 37 times higher density than
other nanoparticles.
Shukla and coworkers [116] investigated on the gold nanoparticles
which are considered nontoxic and can be traced histochemically by
atomic force microscopy (AFM), even ultrastructurally. Such gold
nanoparticles are already in use for diagnostics and pharmaceutical therapy [117121]. Their study supports that only small amounts of gold
nanoparticles are translocated from the lungs. However, SemmlerBehnke reported signicant translocation of smaller (1.4 nm) gold
nanoparticles to the liver (0.7%) [122]. Similarly, they found that translocation of 2 nm particles takes place (only 1.31.9%). Takenaka et al.
treated rats with an aerosol of gold nanoparticles, 58 nm in diameter,
produced by a spark generator [123]. They observed accumulation of
such particles in the pulmonary macrophages and epithelial cells with
a low degree of systemic translocation.
Bhatnagar et al. [124] had conjugated gold NPs with Copper 64
using the macrocyclic chelator (1,4,7,10-tetraazacyclododecane1,4,7,10-tetraacetic acid, DOTA) and polyethyleneglycol (GNP-(64)
Cu/PEG2000) in order to utilize it as a radiotracer for PET and used
it to image T cells. T cells were rst electroporated with DNA plasmids
from the Sleeping Beauty transposontransposase system to coexpress a chimeric antigen receptor (CAR) specic for CD19 and Firey luciferase (ffLuc) was propagated on CD19(+) K562-derived articial antigen presenting cells.
Xiao et al. [125] developed and characterized multifunctional gold
nanorod (GNR) using anticancer drugs doxorubicin to target tumor
cell and imaging by PET. Doxorubicin was covalently conjugated onto
PEGylated GNR nanocarriers via a hydrazone bond to achieve
pH-sensitive controlled drug release which can minimize non-specic
systemic spread of doxorubicin during circulation while maximizing
the efciency of tumor-targeted anticancer drug delivery. It was found
that the cRGD-conjugated GNR nanocarriers showed a higher cellular
uptake. It was concluded that the unique optical properties of
GNRs offer the possibility of using these multifunctional GNR-based
nanoplatform for combined cancer therapies (chemotherapy and
photothermal therapy) and multimodality imaging (PET, optical,
X-ray computed tomography).
4.5. Surface enhanced Raman scattering (SERS)
Surface enhanced Raman spectroscopy or surface enhanced Raman
scattering (SERS) is a surface-sensitive technique that enhances Raman
scattering by molecules adsorbed on metal surfaces and foremost observed for analytes like gold (Au), silver (Ag) and copper (Cu) or alkali
metals like lithium (Li), sodium (Na) and potassium (K). SERS combines
the modern laser spectroscopy with the optical properties of metals

which provide essential structural and surface interface information of
single molecules [126]. Gold NPs due to their optoactive properties
were excellent substrate for SERS. Researchers have been exploring
gold in Raman spectroscopy and surface enhanced Raman scattering
(SERS) for imaging of cancer cells.
Qian et al. [127] explained the biocompatibility and nontoxicity of
gold NPs for in vivo tumor targeting and their detection based on
PEGylated gold NPs and surface-enhanced Raman scattering (SERS).
From the results they revealed that the gold NPs proved to be safe to
treat rheumatoid arthritis and has been found to amplify the Raman
scattering by 1415 orders of magnitude. PEGylated gold NPs were
found to be considerably brighter than the semiconductor quantum
dots. Xie et al. [128] synthesized ower like gold NPs (threedimensional branched nanoparticles with more than 10 tips) with
high yield. Size can be easily varied or adjusted by controlling the reaction mixture. Results of the study showed that gold nanoowers exhibit
strong surface enhanced affects which can be used for efcient, stable
and nontoxic Raman-active tag for in vivo applications.
Jianqiang et al. [129] prepared starch-capped gold NPs with hexagon
and boot shapes using a nontoxic and biologically benign aqueousphase synthetic route. It was found that the shape affects the SERS properties of gold NPs. It was found that boot-shaped nanoparticles can
induce 100-fold SERS enhancements in sensitivity as compared with
gold nanospheres. Finally with these enhanced SERS properties bootshaped nanoparticles can be used as a tool in biolabeling, bioassay,
biodiagnosis, and even clinical diagnosis and therapy.
Ramachandra et al. [130] emphasized the use of gold NPs based
surface-enhanced Raman scattering (SERS) to differentiate the mouse
embryonic stem (mES) cells, undifferentiated single cells, embryoid
bodies (EBs) and terminally differentiated cardiomyocytes. The results
of this study revealed that gold NPs were successfully delivered into
all cell differentiation stages without affecting cell integrity or cell proliferation. Transmission electron microscopy (TEM) studies conrmed
the localization of gold NPs inside the mitochondria, secondary lysosome, and endoplasmic reticulum. Using bright- and dark-eld imaging,
the bright scattering of gold NPs and nanoaggregates in all 3 ES cell differentiation stages could be visualized.
Cristina et al. [131] explained the capability of Raman spectroscopy
to separate the spectral ngerprints of 10 different types of SERS
nanoparticles in a living mouse after subcutaneous injection. The results
revealed that all ve types of SERS NPs were successfully identied and
were spectrally separated. The obtained results demonstrated the high
potential for multiplexed imaging in living subjects in which SERS
probes can provide better detection of biomarkers associated with respective disease.
Keren et al. [132] demonstrate the use of Raman spectroscopy in
noninvasive deep-tissue molecular images in a living subject including in vivo tumor targeting. It was reported that Raman spectroscopy
offers great potential as a strategy tool for biomedical imaging of living subjects. As already discussed in the above review, advances in
nanotechnology lead to more efcient targeted drug delivery of numerous drugs. When it comes to cancer treatment therapy, NPs can
be a promising tool because of its small size that will make NPs easily
perfuse through tumor cells and will retain more time leading to better accumulation of drug [133,134]. Overall NPs prove to be promising in cancer treatment therapy irrespective of chemotherapy and
other techniques to treat cancer which face many limitations like
damage of healthy tissues and dose limiting side effects. Recently
many NP based therapeutics hit the market, whereas many were
under clinical trials or under preclinical development. A good example of NP based therapeutics to treat cancer is Doxil (liposomal formulation of doxorubicin) [135] and Abraxane (paclitaxel-bound
protein particle) [136] which are widely used for treatment of cancer.
Gold NP based cancer therapy basically uses photothermal treatment (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

by maintaining a temperature above 40 C but a temperature above
42 C will cause serious problems like necrosis of cells, and denaturing of enzymes, and may cause functional changes to DNA and lastly
there is a high chance of rupturing of cell membrane leading to the release of cellular content causing death [137142].
Cancer treatment using AuNPs is extensively studied by many researchers [143147]. It was reported that when gold NPs were irradiated
with laser pulses of specied wavelengths targeted nanoparticulate systems like gold nanospheres, nanorods, nanoshells, and nanocages can
kill bacteria and cancer cells [148].
Cobley et al. [149] described the gold nanocages, and plasmonic
nanoparticles, for the treatment of cancer due to their ability to convert light into heat effectively for photothermal treatment. Gold NPs
had provided a new way to treat cancer with minimal side effects.
Au et al. [150] had prepared gold nanocages (65 7 nm average
edge length and 7.5 1 nm diameter) by galvanic replacement reaction using silver nanocubes. Further strong absorption peak at
800 nm was conjugated with monoclonal antibodies (anti-HER2) in
order to target breast cancer cells (SK-BR-3). Photothermal effect
was quantied by ow cytometry. The results clearly revealed that
cells that had been targeted by gold immune cages respond promptly
to laser irradiation. Average number of cell was directly proportional
to the duration of exposure of cells to laser radiation which nally got
steady at 5 min. Thus proper combination of exposure time and optimal dosage of gold nanocages can effectively target tumor cells aiding
for cancer treatment.
Neal et al. [151] studied the feasibility of nanoshell-assisted
photo-thermal therapy (NAPT) as they possess strong near infrared
(NIR) absorption and by their optical absorptivities which can be
modulated according to the need they can go through passive extravasation because of their small size. Photothermal therapy was given
by a diode laser. It was found that after treatment all tumors were
abated and mice appeared to be healthy and tumor free. Study nally
concludes that this simple, noninvasive procedure shows great potential for selective photo-thermal tumor ablation.
Zharov et al. [152] had developed nanoclusters that enhance
photothermolysis of tumor through laser activation. It was reported
that an increase in cell killing was observed. However, a target cell antigen was used in the study to give specicity to nanoclusters to make
cancer cell sensitive to laser which will make this therapy more
effective.
Letfullin et al. [153] studied gold nanoclusters that will be
transported to the target cancer cells either through physical transportation or through conjugating with antibodies or virus. After
reaching the target site, these gold nanoclusters will be irradiated
with short laser pulses of sufcient energy that will make these
nanoclusters to explode. As concluded the explosion of these particles
may be accompanied by optical plasma, shock wave generation and
particle fragmentation, which collectively aid in killing of cells.
Zharov et al. [154] have investigated on gold nanoclusters conjugated with specic antibodies (anti-protein A antibodies) and laser
was subjected upon them which makes the particle explodes, killing
targeted bacteria (Gram-positive bacterium Staphylococcus aureus).
This approach provides a real time achievement in the therapeutic
area. Strong laser induced over heating effects accompanied by the
bubble formation around the gold NPs are the main reason for bacterial damage which are clearly visualized by photothermal imaging.
Stern et al. [155] have reported that 5000 gold nanoshells per
prostate cancer cells can kill cancer cells. Patra et al. [156] clearly
demonstrated the potential of gold NPs as a drug delivery adjuvant
for the treatment of pancreatic cancer. Gold NPs were covalently
bounded to cetuximab, as an active targeting agent and gemcitabine
as a therapeutic molecule in the therapy. It was reported that gold
NPs can be utilized effectively for targeted drug delivery in the pancreatic cancer.
Patra et al. [157] developed a delivery system containing gold NPs

using cetuximab as a targeting agent, and gemcitabine as an anticancer drug and studied it's in vitro application against three pancreatic
cancer cell lines (PANC-1, AsPC-1 and MIA Paca2). The results revealed that the above system exhibits signicant inhibition of pancreatic cell proliferation engrossed with cancer. It was concluded that
gold NPs in combination with other agents can be used as a promising
approach to treat variety of cancers.
Jiang et al. [158] produced gold and silver NPs coated with antibodies that can regulate the process of membrane receptor internalization. It was found that the binding and activation of membrane
receptors and subsequent protein expression strongly depend on
the nanoparticle size. The obtained results revealed that NP size
range from 40 to 50 nm showed a profound effect. These results collectively showed that gold NPs can be a useful core material to promote biological effects.
Huo et al. [159] have developed a facile nanoparticle immunoassay for serum protein biomarker detection and analysis using gold
nanoparticles coupled by dynamic light scattering. Using the above
assay on both mice and human blood serum samples they discovered
multiple molecular aberrations associated with prostate cancer. This
study revealed that there is a difference in protein corona and
mouse IgG level between different mice groups (i.e., mice with aggressive or less aggressive prostate cancer, and normal healthy controls). It was found that the level of vascular endothelial growth
factor (VEGF, a protein that is mainly associated with tumor angiogenesis) is decreased in cancer samples. Thus this method proves to
be successful in utilizing biomarkers for prostate cancer and can be
used to analyze serum protein. Recently, Fujita et al. investigated on
the time-resolved acquisition of the SERS spectra and also allowed
observation of the transport of AuNPs via a living cell [160]. Furthermore, researchers can use it in order to develop new biomarkers associated with cancer and other human diseases.
5. Radioactive isotopes of gold

Currently radioactive isotopes have been widely used for medical
treatment such as cancer therapy with continually growing interest.
Diagaradjane et al. [161] investigated the gold nanoshells for
noninvasive modulation of in vivo tumor radiation response. A reduction in hypoxic fraction of tumors was found which was noninvasively quantied by magnetic resonance temperature imaging.
An increase in radiation dose induces vascular disruption with extensive tumor necrosis. This study indicates that a novel integrated
antihypoxic and localized vascular disrupting therapy which can be
combined with other antitumor therapies for better cancer treatment
therapy.
Recent literature reported the use of gold (Au 198 colloid) for the
treatment of pleural and peritoneal effusions due to neoplastic inltration which was considered as an effective therapy as recurring effusions necessitate repeated aspirations [162164]. In other approach
small gold grains had been employed for the treatment of carcinoma
of the pancreas and to treat wide variety of tumors throughout the
body. It was reported that radioactive isotopes of short half-life can
be easily employed for permanent implants and radioactive isotopes
of longer half-life can be used for temporary implants [165].
Nripen et al. [166] have prepared gum arabic glycoprotein (GA)functionalized gold NPs and investigated their biocompatibility and
therapeutic applications in cancer. It was revealed that gold NPs
(1218 nm) can easily target the tumors and can penetrate into
tumor cells. It was found that -emitting gold-198 (198Au) shows high
afnity for severely compromised immunodecient (SCID) mice having
human prostate tumor xenografts. A single dose administration of 198Au
resulted in drastic regression and revealed effective therapeutic control
on growth of prostate tumors over 30 days.
dx.doi.org/10.1016/j.cis.2013.06.003
10
6. Role of gold NPs in DNA plasmid studies

DNA plasmid model is a simple system that helps scientists to understand the effect of radiation induced damage and free radical effects on cells. Plasmid DNA is a double stranded extrachromosomal
DNA that is normally present in bacteria. This system allows to assess
the sensitization measurement of gold NPs without biological intervention in cells and without DNA damage [167,168].
Carter et al. [169] have investigated the distribution of energy release from the gold NPs to determine the distance for sensitization to
occur. They performed a Monte Carlo calculation and laid some ndings for the phenomena to occur. Firstly by enhanced absorption of
X-rays by gold NPs, secondly effective release of electrons with
low energy and lastly deposition of energy in water (radicals and
electrons). This study also revealed the theoretical based nanoscale
energy disposition distribution underlying the gold-based sensitization mechanisms.
Another study reported by Boudaiffa et al. [170] had thrown some
light on the damage of DNA. They reported the measurements of the
formation of single, double and multiple strands that breaks in pure
plasmid DNA after exposing them to 1050 eV electrons. It was noticed that very low energies which directly cannot ionize DNA were
responsible for DNA damage. They reported that damage of DNA occurs through a mechanism named as dissociative electron attachment
(DEA) where the electrons get attached to DNA after exposure to
electrons where they resonate and forms a transient molecular
anion which nally leads to fragmentation. The plasmid model allows
measurement of sensitization without the biological interactions of
AuNPs with cells and without the impact of DNA repair.
Zheng and Sanche [171] have reported that there will be an enhanced radiation damage upto a magnitude of (7.5 units) when two
cisplatin molecules and one gold NP were bound to plasmid DNA.
Butterworth et al. [172] have assessed the effect of size and scavenging conditions on radio sensitization. They characterized cellular cytotoxic range of cell lines to 1.9 nm gold NPs. It was found that gold NPs
caused signicant levels of cell type specic cytotoxicity, apoptosis
and increased oxidative stress. When used as dose modifying agents it
was found that dose enhancement factors varied between the cell
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 noticed that 1.9 nm gold NPs lead to cell line response like a decrease in
clonogenic survival rate, increased apoptosis and DNA damage which
might be induced as the results of production of reactive oxygen
species. This study lled a loophole for extensive and in-depth characterization of gold NPs when measuring dose enhancing potential in cancer therapy which will be highly useful for the researchers of plasmid
DNA damage study.
Conde et al. [173] have developed a gold NP based approach for
molecular recognition and quantication of the BCRABL fusion transcript (mRNA), which is responsible for chronic myeloid leukemia
(CML). It was reported that the above method is the rst of its kind
that is used for time quantication of a specic mRNA directly in cancer cells and is inexpensive and easy to use. Coming to sensitivity, it
was found that the developed gold nanoprobes allow differential
gene expression from 10 ng/L of total RNA and take less than
30 min to complete after total RNA extraction, minimizing RNA degradation thus making it an excellent tool for early diagnosis of CML.
The DNA plasmid studies can yield useful information about the
mechanisms by which sensitization can occur and guide the design
of in vitro and in vivo experiments.
7. Gold nanoparticles as an antioxidant
It was reported that oxidative stress and reactive oxygen species
(ROS) were found to be crucial in a variety of diseases such as diabetes,
cancer etc [174]. Yakimovich et al. [175] synthesized gold containing
nanocomposites by UV irradiation followed by the thermal treatment

of chitosan oligomer solutions doped by HAuCl4. It was reported that
the antioxidant activity of the gold nanoparticles with respect to hydroxyl radicals considerably depends on the specic surface area of
the NPs.
Nie and co-workers [176] laid special emphasis on alpha-tocopherol
(vitamin E) as a starting material to synthesize new synthetic antioxidants with improved properties. Because of its potent antioxidant function and important role in clinical treatment alpha-tocopherol can be a
useful base for new antioxidant. The antioxidant-functionalized gold
nanoparticles, Au@Trolox, was rst synthesized by self-assembly of
thiol ligands that has been derived from Trolox, a vitamin E analogue,
on gold NPs. (2,2-diphenyl-1-picrylhydrazyl). Results were positive
and it was concluded that the assembly of chromanol groups on gold
NPs could efciently enhance the activity of the vitamin E-derived antioxidant which can lead to the development of many synthetic antioxidant that can be benecial in many aspects.
Yin et al. [177] have stated that [Gd@C82(OH)22]n (endohedral
metallofullernol) NPs can be a useful scavenger for ROS as it reduce
the generation of ROS to an extent by production phase II enzymes
which are closely associated with destruction and metabolism of ROS
species. Barath et al. [178] had studied the effect of biologically synthesized AuNPs on hyperglycemic conditions in streptozotocin induced diabetic mice. It was found that gold NPs exhibited an excellent control
over the blood glucose level, lipids and serum biochemical proles in diabetic mice that were nearly equal to control mice blood glucose level.
Histological studies (liver and pancreas) that had been done for the
four groups control, diabetic control, diabetic control treated and gold
treated clearly revealed that gold NPs help in recovering of organs to
normal histology by keeping a check on ROS generation and inhibition
of lipid peroxidation as shown in Figs. 7 and 8. Results clearly showed
that gold NPs can be a promising candidate for antioxidant action, as
they inhibit the formation of ROS, scavenging free radicals, thus increasing the anti-oxidant defense enzymes of the body and creating a
sustained control over hyperglycemic conditions that will prove to be
very benecial in diabetic treatment.
8. Gold nanoparticles as biosensors
Nanotechnology plays a key role in the development of biosensors. The run is on continuously improving biosensor sensitivity and
performance by using suitable nanomaterials for the fabrication
which allows induction of many new signal transduction technologies in biosensors. Because of their small size nanosensors proved to
be a promising tool for simple and rapid analyses in vivo. Inorganic
nanoparticles bound with biological moieties (protein and peptides)
have been developed in order to detect and amplify signals.
Maxwell et al. [179] have utilized colloidal gold nanocrystals to develop nanobiosensors that are able to recognize and detect specic
DNA sequences and single-base mutations. 2.5 nm gold NPs in the core
of biosensor function as both a nano-scaffold and a nano-quencher is attached with oligonucleotide molecules labeled with a thiol group at one
end and a uorophore at the other. However, the binding of core molecule results in conformational change and this restored the uorescence
of the quenched uorophore. They reported that the biosensor developed was efciently able to detect single-base mutations in a homogeneous format. Cai et al. [180] investigated the use of colloidal gold to
enhance the DNA immobilization on a gold electrode and to ultimately
lower the detection limit of our electrochemical DNA biosensor. Colloidal
gold of 16 nm diameter was assembled onto a cysteamine modied gold
electrode which eases the attachment of an oligonucleotide with a
mercaptohexyl group at the 5-phosphate end, and therefore an increased capacity for nucleic acid detection. They showed that the surface
densities of oligonucleotides on the Au colloid modied gold electrode
were approximately (14) 1014 molecules cm2. It was concluded
that Au nanoparticle lms on the Au electrode provide a novel
dx.doi.org/10.1016/j.cis.2013.06.003
11
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
12
Fig. 9. Schematic representation of PEG coated gold nanoparticles.
means for sequence-specic DNA (ssDNA) immobilization and ssDNA

detection.
Glucose oxidase, horseradish peroxidase, xanthine oxidase, and
carbonic anhydrase have been adsorbed to colloidal gold sols. It was
found that there is no change in enzymatic activity of xanthine oxidase after adsorption on colloidal gold as determined by active site
titration with the stoichiometric inhibitor pterin aldehyde and by
measurement of the apparent Michaelis constant (K(M)). Further
these gold sols which previously adsorbed with glucose oxidase,
horseradish peroxidase, and xanthine oxidase are electrodeposited
onto conducting matrices like platinum gauze and glassy carbon in
order to make enzyme electrodes which not only retain enzymatic activity but also serve as a path to gave an electrochemical response to
the enzyme substrate in the presence of an appropriate electron
transfer mediator [181].
Xu et al. [182] investigated the direct electrochemistry of horseradish peroxidase (HRP) that is immobilized on a colloidal gold modied screen-printed carbon electrode (HRP-Au-SPCE). Immobilized
HRP displayed a couple of stable and well-dened redox peaks with
a formal potential of 0.338 V and a heterogeneous electron transfer
rate constant of 0.75 0.04 s1. It showed a highly thermal stability,
fast amperometric response and an electrocatalytic activity to the reduction of hydrogen peroxide (H2O2) without the aid of an electron
mediator. Biosensor developed exhibited high sensitivity, good reproducibility, and long-term stability for the determination of H2O2.
Gold NPs serve as excellent uorescence quenchers for FRETbased assays due to its high molar extinction coefcients and broad
energy bandwidth [183184]. Precisely FRET based gold NPs prove
to be an extraordinary bio-tool for sensing small organic molecules.
Thiols at submicromolar levels have been detected by gold NPs
which are non-covalently attached to the nile red [185]. Tang et al.
have developed a FRET based cholesterol sensor by using -cyclodextrin (-CD) functionalized AuNPs [186]. Nanocomposite gels of gold
NPs/chitosan have been used for electrochemical monitoring of adhesion, proliferation, and apoptosis of cells on the glassy carbon electrode (GCE) which showed an irreversible voltammetric response
and enhanced the electron transmittance with a limit of detection of
8.71 102 cells/mL [187]. Electrocatalytic sensor to identify tumor
cells specically has been developed by de la Escosura-Muniz. Antibodies conjugated with gold NPs were used to identify molecules on
cell surface by catalytic hydrogen reduction [188]. Gold NPs conjugated with DNA have been used on GCEs using methylene blue (MB) as
an electroactive label and differential pulse voltammetry (DPV) for DNA
sensing. Results revealed that there was an enhanced signal response
during immobilization and hybridization [189]. It was investigated
and proved that gold based electrochemical immunosensors enhance

the electrochemical signal transduction of the binding event between
antigen and antibody which in turns provide better surface for
immunoreagent stability upon immobilization [190]. A variety of
small carcinogenic substances like, Aatoxin B1, [191], Ocra-toxin A,
[192], naphthalene [193], herbicides picloram [194] and hormones
like human chorionic gonadotrophin have been detected by gold
based electrochemical immunosensors.
9. Toxicity related aspects of gold nanoparticles
Gold in its bulk form has long been considered an inert, noble
metal with some therapeutic and even medicinal value hence Au
NPs had been widely used in drug delivery, biomedical applications
like imaging and diagnosis of many diseases as it was found to be
nontoxic, and biocompatible thus making it suitable for many of
medical applications like wires in pacemakers, intravenous contrast
agent for imaging and noninvasive detection of lung cancer [195].
Much research had been done in this area which conrms the
nontoxicity of gold NPs [196198]. However, on contrary some
conicting researches are present which revealed the toxicity of
gold NPs. Yu et al. [199] had prepared water soluble gold NPs (0.8
to 15 nm) stabilized with triphenylphosphine derivatives and carried
out a cytotoxicity test in four cell lines that represent major functional
cell types. It was found that cellular responses were size-dependent
and revealed that 1.4 nm particles cause predominantly rapid cell
death by necrosis within 12 h and 1.2 nm causes cell death by apoptosis. Dong et al. [200] investigated the irradiation effects on gold
NPs and cytotoxicity of gold NPs with human K562 cells using cell
Titre-Glo luminescent cell viability assay. Results revealed that
gold NPs show excellent radiation hardness and revealed a concentration dependent toxicity in cell lines. It was found that extremely
high concentration of gold NPs will cause a sharp decrease in K562
cell viability, whereas a low concentration of gold NPs showed no
inuence on the cell viability. Sung et al. [201] studied the toxicity of
gold NPs in Sprague Dawley rats by inhalation. Study includes cellular
differential counts and cytotoxicity measurements, such as albumin,
lactate dehydrogenase (LDH), and total protein in cellular bronchoalveolar lavage (BAL) uid. The obtained results revealed that there was
no statistical difference in cellular differential counts however, histopathologic results showed minimal alveoli, an inammatory inltrate
and increased macrophages in the rats which were highly dosed.
Abdelhalim and Jarrar [202] investigated the effect of gold NPs on
hepatic tissue by 50 or 100 ul of gold NP infusion of size (10, 20 and
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
13
Table 1
Various studies carried out using Gold NPs for biomedical applications.
Authors
Preparation method
Size
Results
Type of
nanosystem
utilized
Year and
reference
Zhang et al.,
0.01% chloroauric acid (HAuCl44H2O)

solution is reuxed and 5 mL of 1%
sodium citrate solution added to the
boiling solution.
Gold NPs formed due to the reduction
of gold ions by citrate ions.
0.01% chloroauric acid (HAuCl44H2O)
solution is reuxed and 5 mL of 1%
sodium citrate solution added to the
boiling solution. Gold NPs formed due
to the reduction of gold ions by citrate
ions as shown in Fig. 9
13.5 nm
Results conrmed that gold nanoparticles

at low concentrations do not cause
appreciable toxicity even after their
breakdown in vivo over time.
Nanospheres
2010, 191
5 to 60 nm
Nanospheres
2011, 198
Dioctyl sulfosuccinate sodium salt (AOT)/

water/hexane reverse system by reduction
of gold chloride with hydrazine hydrate.
Gold NPs were prepared using sodium
citrate with chloroauric acid
(HAuCl44H2O) solution
100 nm long
with diameter
20 nm
30 nm
Nanorods
2011, 203
Nanospheres
2011, 204
Puiyan Lee,
Lipidic gold porphyrin nanoparticles

were prepared using oil in water (o/w)
microemulsion technique
80 30 nm
Nanospheres
2010, 205
Etame et al.,
Sodium citrate employed with sodium

borohydride was used to generate
particles of less than 10 nm
424 nm
Nanospheres
2011, 206
Juan Gu et al.,
Gold-doxorubicin nanoconjugates were

developed by grafting doxorubicin (DOX)
onto polyethylene glycol (PEG)-modied
gold (Au) nanoparticles (Au-NPs) via
cleavable disulde (SS) linkage.
16.2 to 28.2 nm
Size-dependent in vivo toxicity study of

PEG-coated gold NPs in mice was carried
out which revealed that 5 nm and 10 nm
particles mainly accumulate in the liver,
and that the 30 nm particles mainly
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.
Gold nanorods may be used to kill cancerous
cells in tumor in rat tissue when
subcutaneously injected.
Results demonstrated that even a small
tumor, that remain untraceable through
anatomical computed tomography,
becomes clearly visible by the
molecularly-targeted gold nanoparticles
Incorporation of gold porphyrin into lipidic
nanoparticles resulted in a 16-fold increase
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.
It is reported that short PEG chain length
(molecular weight 10002000) in
combination with smallest core size led to
optimum permeation in tumor vasculateure.
Gold nanoparticles can be successfully
applied to overcome multiple drug resistance
(MDR) in cancer chemotherapy.
Nanoconjugate
2012, 207
Zhang et al.,
Samim et al.,
Reuveni et al.,
found that gold NPs had produced changes in hepatocytes, portal triads
and sinusoid integrity which may be due to accumulated residues
resulting from metabolic and structural disturbances caused by these
gold NPs. Alterations are in terms of hydropic degeneration, cloudy
swelling, fatty degeneration, portal and lobular inltrate by chronic inammatory cells and congestive dilated central veins as reported. Study
results revealed that these alterations are size dependent with smallest
size causing most profound effects with exposure time dependency.
Table 1 addresses some of the current studies that have been carried
out by utilizing gold NPs as a tool for biomedical applications.
10. Conclusion
Gold nanoparticles have shown great promise for the development
of drug delivery by various routes of administration and made a great
impact on clinical applications like imaging, diagnosis, and therapeutic radio sensitizers. They are small and can penetrate widely throughout the body, preferentially accumulating at tumor sites owing to the
EPR effect. AuNPs exhibit unique physico-chemical properties including surface plasmon resonance (SPR). The surface modication or
functionalization widens the application window of the AuNPs. Importantly, they can bind many proteins and drugs and can be actively
targeted to cancer cells over expressing cell surface receptors. The development of gold nanoparticles offers researchers a huge platform for
introducing gold in several therapeutic applications even at intracellular level also that will help in improvising the care of patients. Clinical
implications of gold nanoparticles are found to be promising and
much more researches are still going on regarding gold as a therapeutic candidate especially in the eld of cancer. The uniqueness of providing combinational therapy made gold NPs a promising approach
in order to resolve cases of many life threatening diseases.
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Gold Nanoparticles - A Paradigm Shift in Biomedical Applications

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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

Available online xxxx

(FDA) for the use and development of nanotechnology-based drugs in

oscillation. Detection of biological events at the single molecule

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

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

3.3. Gold nanoshells

Oldenburg and coworkers [61] were rst to develop silica-core

are highly suitable for biomedical applications. Gold NPs possess a

coherence tomography (OCT). Gold nanoshells were administered

60 nm) were found to be stable in physiological conditions and are

the modern laser spectroscopy with the optical properties of metals

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

5. Radioactive isotopes of gold

6. Role of gold NPs in DNA plasmid studies

nanocomposites by UV irradiation followed by the thermal treatment

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

0.01% chloroauric acid (HAuCl44H2O)

Results conrmed that gold nanoparticles

Dioctyl sulfosuccinate sodium salt (AOT)/

Lipidic gold porphyrin nanoparticles

Sodium citrate employed with sodium

Gold-doxorubicin nanoconjugates were

Size-dependent in vivo toxicity study of

Ju H, Roy RA, Murray TW. Biomed Opt Express 2013;4(1):6676.

Kang JW, Li XN, Wu GF, Wang ZH, Lu X. Anal Biochem 2007;364:165.

Yu P, Sabine N, Annika L, Monika F, et al. Small 2007;3:19419.

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