Acta Pharmacologica Sinica (2011) 32: 983–990 npg

© 2011 CPS and SIMM All rights reserved 1671-4083/11 $32.00

www.nature.com/aps

Review

Gold nanoparticles in cancer therapy

Zhao-Zhin Joanna LIM1, Jia-En Jasmine LI1, 2, Cheng-Teng NG1, 2, Lin-Yue Lanry YUNG2, *, Boon-Huat BAY1, *
1
Department of Anatomy, National University of Singapore, Singapore; 2Department of Chemical and Biomolecular Engineering,
National University of Singapore, Singapore

The rapid advancement of nanotechnology in recent years has fuelled a burgeoning interest in the field of nanoparticle research, in
particular, its application in the medical arena. A constantly expanding knowledge based on a better understanding of the properties
of gold nanoparticles (AuNPs) coupled with relentless experimentation means that the frontiers of nanotechnology are constantly being
challenged. At present, there seems to be heightened interest in the application of AuNPs to the management of cancer, encompass-
ing diagnosis, monitoring and treatment of the disease. These efforts are undertaken in the hope of revolutionizing current methods
of treatment and treatment strategies for a multifactorial disease such as cancer. This review will focus on the current applications of
AuNPs in cancer management.

Keywords: gold nanoparticles; cancer therapeutics; cancer diagnosis; photothermal therapy; radiation therapy

Acta Pharmacologica Sinica (2011) 32: 983–990; doi: 10.1038/aps.2011.82; published online 11 Jul 2011

Introduction In light of the shortcomings of current treatment modalities

According to the World Health Organization (WHO), cancer for cancer, a critical thrust towards improving cancer therapy
accounted for 7.9 million deaths in 2007 making it the lead- is to specifically target therapeutic agents to tumor cells while
ing cause of death in the world. Deaths from cancer around sparing healthy tissues from harm. This is one of the emerging
the globe are expected to climb upwards with an estimated interests in nanotechnology research. Nanotechnology refers
12 million deaths by cancer in 2030[1]. The frontiers of can- to the manufacture of materials having nanoscale dimensions
cer research are therefore consistently challenged in order to between 1 nm and 100 nm[4]. The small size of these nano-
advance the most effective means of cancer diagnosis, moni- materials confers their uniqueness with chemical and physical
toring and treatment. Findings gleaned from cancer research properties that are distinct from their bulk materials[5]. The
would inevitably benefit mankind and save countless lives. rapid expansion in nanomaterial research increases the future
Current therapies employed for the treatment of cancer prospect of novel diagnostic methods and treatment of dis-
include surgery, chemotherapy and radiation therapy among eases that plague mankind. This branch of nanotechnology in
others. While these methods have been accepted and prac- disease diagnosis, monitoring and treatment has been termed
ticed for decades, they have their drawbacks and side effects. “nanomedicine” by the National Institutes of Health in the
Surgical removal of tumors is restricted mainly to large, resec- USA[4].
table and accessible tumors. Chemotherapeutic drugs target Among the many nanomaterials being developed for nano-
rapidly dividing cells, and thus not only kill cancer cells, but medicine applications, this review will focus on gold nano-
also destroy normal cells like bone marrow cells and immune particles (AuNPs) and their potential as tumor sensors, drug
cells[2]. This gives rise to widespread “collateral damage” in delivery agents and enhancers in plasmonic photothermal
the patient’s body. Radiation therapy involves the use of high- therapy for the eradication of cancers. The use of AuNPs is
energy radiation like X-rays and gamma rays to destroy tumor gaining popularity in these areas of research for several rea-
cells, and inevitably causes deleterious effects to healthy tis- sons. Firstly, AuNPs are considered to be relatively biologi-
sues along the radiation path[3]. cally non-reactive and therefore suitable for in vivo applica-
tions compared to the very toxic cadmium and silver NPs[6]
* To whom correspondence should be addressed. although various groups (as explained in the later sections) are
E-mail [email protected] (Boon-Huat BAY); challenging this view. Other advantageous qualities include
[email protected] (Lin-Yue Lanry YUNG) the strong optical properties of AuNPs due to localized sur-
Received 2011-01-18 Accepted 2011-05-23 face plasmon resonance (LSPR)[7], easily controllable surface
 www.nature.com/aps
npg Lim ZZJ et al
984

chemistry which enables versatility in adding surface func- concomitant down-regulation of cell cycle genes such as
tional groups[8], and lastly, the ease in control over particle size Cyclin B2 and B1 and DNA damage response genes. In a
and shape during synthesis[9]. AuNPs may be considered to follow-up study, the same investigators observed the presence
be fully multifunctional, with the possibility of combining dif- of autophagy (validated by biochemical and morphological
ferent desired functionalities in one molecular-sized package. parameters) concurrent with oxidative stress in the lung fibro-
All these factors contribute to the strong interest and prefer- blasts following uptake of AuNPs[25]. It was also demonstrated
ence for the use of AuNPs over other NPs [10]. Examples of in the same study that AuNP treatment led to the up-regula-
other nanomaterials for biomedical applications can be found tion of antioxidants and expression of stress-response genes
in other published papers which expound on the utilization of and proteins, lending support to the hypothesis that oxidative
quantum dots[11, 12], functionalized fullerene-based nanomateri- stress could be a manifestation of AuNP cytotoxicity.
als[13] and magnetic NPs[14, 15] for the diagnosis and treatment of
human diseases. In vivo studies on cytotoxicity of AuNPs
In a recent study, blue mussel Mytilus edulis was observed
AuNPs and cytotoxicity to experience oxidative stress within 24 h of exposure to
As the utility of AuNPs largely depends on the degree of AuNPs[26], indicating the possible impact of AuNPs to the eco-
inherent toxicity, studies on the toxicological profile of these system and aquatic animals. The same investigators also pro-
NPs are discussed proceeding to their usage in cancer man- posed the use of M edulis as an ideal animal model for envi-
agement. Since NPs exhibit properties which are markedly ronmental toxicology studies of NPs. Another in vivo study
different from that of their much larger counterparts, their utilized zebrafish embryos to assess the feasibility of AuNPs as
behaviour and effects cannot be extrapolated from informa- probes for embryonic imaging[27]. In this study, the real-time
tion derived from their bulk materials. Bulk gold has gen- effects of AuNPs on zebrafish embryos were investigated, and
erally been considered an inert metal valued for medicinal results showed that owing to the random diffusion of AuNPs
purposes[16] and AuNPs have been thought to be likewise. In to various parts of the embryo, toxic effects influencing the
the literature, AuNPs have been reported to lack the ability to developmental outcome of the embryo were largely stochastic
induce adverse and acute toxicity[17] and are thus deemed to be in nature. Among the 76% of zebrafish embryos that survived,
biocompatible entities for use in biomedical applications[17, 18]. only a minority (2%) of zebrafish embryos exhibited defor-
However, recent studies have shown that there could be more mities while the remaining 74% developed normally. The
to AuNP toxicity than already surmised and that the extent authors therefore proposed that given its relatively non-toxic
of toxicity response is closely associated with the size of the nature, AuNPs could be exploited for in vivo imaging applica-
AuNPs[19, 20]. Investigations have revealed that decreasing the tions for embryonic studies.
size of NPs correlated with more widespread tissue distribu- For mammals, however, there is at present limited informa-
tion, heightened potential to deeper penetration within certain tion regarding the in vivo toxicity of AuNPs. Studies have
tissues, more effective internalization by cells, and increased largely focused on the biodistribution of AuNPs in the body.
toxic effects[21]. In terms of surface functionality, studies have A rat model study revealed the size-dependent organ distribu-
shown that modification of the AuNP surface affect its uptake, tion of AuNPs following intravenous (iv) administration. For
interactions with cellular constituents and cytotoxicity[22, 23]. 10 nm AuNPs, the distribution was found to be widespread,
permeating the blood and organs of the cardio-respiratory
In vitro studies on cytotoxicity of AuNPs system, immune system (such as spleen and thymus) and
Multiple studies have shown that AuNPs exert their cytotox- reproductive system, liver, kidney, and brain, whereas larger
icity through the induction of oxidative stress. For example, AuNPs (50, 100, and 250 nm) were localized only to the blood,
when exposed to 1.4 nm AuNPs, HeLa cervical carcinoma cells liver and spleen[28]. A similar study conducted using 15, 50,
exhibited increased reactive oxygen species (ROS) production 100, and 200 nm AuNPs showed that while the AuNPs with
and oxidative stress, leading to protein and lipid oxidation, the largest dimension could only accumulate minimally in
severely impaired mitochondrial function, and eventually cell organs following iv administration into mice, AuNPs with
death[23]. The same investigators showed that Z-VAD-fmk, a the smallest dimension were detected in all tissues including
caspase inhibitor was unable to rescue the cells from dying, blood and other organs such as the liver, lung, spleen, kidney,
leading to the conclusion that cells were killed by necrosis. brain, stomach, and heart[29]. The results imply that smaller
Furthermore, genome-wide mRNA expression analysis veri- size AuNPs are more accessible to various tissues in the body
fied that treatment with AuNPs caused up-regulation of and therefore the propensity to cause widespread harm, if any.
stress-related and inflammation-related genes and a concomi- Another group of researchers assessed the in vivo toxicity
tant decrease in the expression of cell cycle genes. It appears of 13 nm AuNPs coated with poly (ethylene) glycol (PEG) in
that continual production of endogenous ROS within the cell mice and showed that following iv injection of AuNPs, the
exhausted the intracellular antioxidant pool and therefore NPs accumulated in mouse liver and spleen for up to a week,
induced irreversible damage that eventually lead to necrosis. and induced acute inflammation and apoptosis in the liver[30].
Oxidative stress was observed in MRC-5 fetal human lung The same group of investigators also demonstrated that iv
fibroblast cells following exposure to 20 nm AuNPs[24] with administration of 4 nm or 100 nm PEG-coated AuNPs in mice

Acta Pharmacologica Sinica

 www.chinaphar.com
Lim ZZJ et al
npg
985

induced up-regulation of common genes associated with spectroscopy (SERS) imaging of tumor biomarkers which are
apoptosis, cell cycle, inflammation, and metabolic process in overexpressed in MCF7 breast cancer cells[35]. Raman scatter-
liver tissues[31]. ing is a phenomenon that results from the inelastic collision
A major challenge in the field of investigating in vivo cyto- of photons with molecules where energy, which is either lost
toxicity of NPs is the plausibility of translating observed cel- or gained, translates to a change in the frequency of the scat-
lular and immunological toxicity in animal models to humans, tered photons. This unique shift of frequency depends on the
since there are distinct intra- and interspecies variations which characteristic energy of molecular vibrations constituting the
need to be considered. signal, hence a Raman spectrum consisting of different signals
from molecular vibrations forms a “vibrational fingerprint”
Applications of AuNPs in cancer management of a molecule[36]. In SERS, these Raman signals are amplified
AuNPs as sensors for probing and imaging tumor cells several folds by nanostructures present in the vicinity of the
AuNPs are good candidates for labelling applications because molecules. Gold and silver have been shown to cause signifi-
of their ability to interact strongly with visible light. Upon cant enhancement[37] and are thus the favoured nanostructures
exposure to light, free electrons in gold atoms are excited to a used as sensors[24]. By attaching a reporter to SERS sensors,
state of collective oscillation known as surface plasmon reso- targeted sensitive probing of molecules or structures within
nance (SPR), conferring gold the ability to absorb and scatter cells may be achieved[36].
visible light[32]. In labelling applications, AuNPs are targeted Recent studies have demonstrated the potential use of
and accumulated at the site of interest and based on their AuNPs for in vivo targeted imaging of cancer using Raman
optical scattering properties, they enable visualization of the spectroscopy. Large optical enhancements can possibly be
region under study. AuNPs may then be detected by any of achieved in the detection of tumors in live animals owing
the following ways: phase contrast optical microscopy, dark to the 14–15 orders of magnitude signal amplification by
field microscopy, photothermal imaging, and photoacous- AuNPs[38]. Following the conjugation of AuNPs with appro-
tic imaging[33]. In addition, owing to its high atomic weight, priate ligands, cancer markers such as epidermal growth factor
AuNPs remain the preferred label for visualization and receptors present on the surface of human cancer cells and in
immuno-staining at the ultrastructural level using transmis- xenograft tumor models could be targeted for detection. This
sion electron microscopy[34]. shows the potential of using AuNPs for biomedical imaging
A crucial step in successful cancer therapy involves early in live subjects. However, it is important to note that the suc-
diagnosis. The strong optical scattering properties of AuNPs, cessful optical imaging performed in mice cannot be directly
coupled with their relative biocompatibility, make them scaled up for in vivo imaging of human subjects because the
suitable as probes for cancer imaging. Through the conju- optical signals possess limited tissue penetration ability[39]. At
gation of antibodies specific for antigens overexpressed on present, optical imaging only appears useful for tissues close
tumor cells, AuNPs can be directed to tumor cells, thus pin to the skin surface or accessible by endoscopy. Hence, addi-
pointing their precise location in the body (Figure 1). It has tional technological improvements are needed before Raman
been demonstrated that antibody-conjugated hollow gold scattering by AuNPs can be used in a clinical setting.
nanospheres can be used for the surface-enhanced Raman The utility of AuNPs as novel biosensors for the detection of
tumor cells can be demonstrated through the use of a screen-
printed carbon electrode (SPCE) coupled with a NP-based
electrocatalytic method[40]. Using this technique, in situ tumor
cell proliferation was detected and quantified via the reaction
of cell surface proteins with specific antibodies conjugated to
AuNPs. Human tumor HMy2 cells (human leukocyte antigen
(HLA-DR) class II positive B cells) and human tumor PC-3
cells (HLA-DR class II negative prostrate carcinoma) were first
grown on the surface of SPCEs, following which they were
incubated with a commercial monoclonal antibody (mAb) spe-
cific to DR molecules conjugated to AuNPs (direct method) or
unconjugated mAb followed by secondary antibodies conju-
gated to AuNPs (indirect method). When hydrogen ions were
catalytically reduced to hydrogen in the presence of AuNPs,
the amount of AuNPs (and thus a corresponding indication of
the quantity of attached tumor cells) could be quantified. In
both methods, the AuNP immunosensor was able to distin-
guish DR-positive tumor cells from DR-negative tumor cells,
Figure 1. Schematic diagram showing the localization of antibody showing the efficiency of this novel biosensor in detecting spe-
conjugated gold to receptors present on the plasma membrane of cells. cific tumor cells.

Acta Pharmacologica Sinica

 www.nature.com/aps
npg Lim ZZJ et al
986

AuNPs as drug delivery agents targeted to cancer cells a combination of these methods. Thus far, the in vitro works
A prominent application of AuNPs is their use as vehicles for done by Kim et al[9] have yielded promising results. However,
delivery of molecules into cells. AuNPs have been described more work is required as there is still the need to assess if
as “promising nanocarriers for therapeutics” owing to their these methods are practical for application in vivo.
ease of synthesis and functionalization, relative biocompatibil- Similarly in the field of cancer therapy, AuNPs are cur-
ity[41] as well as low toxicity in preliminary assays[9]. However, rently being explored as potential drug delivery agents for the
various factors need to be considered in designing an effective introduction of drugs into tumor cells[49]. Cells are known to
drug delivery system. The properties of AuNPs such as their take up colloidal AuNPs of various shapes and sizes[22] either
size, charge and surface chemistry have been shown to affect by specific (via ligand-receptor interaction) or non-specific
the uptake of AuNPs into cells as well as their subsequent means. An example of AuNPs being taken up by breast
intracellular fate. In addition, effective drug delivery strate- cancer cells in vitro is shown in Figure 2. In order to ensure
gies must take into account the nature of drug-AuNP interac- the specific killing of cancer cells while sparing healthy cells,
tion (covalent/non-covalent binding) as well as the means AuNPs were conjugated with appropriate surface ligands
of drug release following introduction of the drug-AuNP which directed them only to tumor cells (Figure 3). Huang et
complexes to cells[42]. If AuNPs are used solely as carriers into al (2008) have described two methods for tumor targeting: the
cells, it is also critical to monitor any toxic effects of residual first involved conjugation of AuNPs to PEG, and the second
materials in the cell after delivery; a biodegradable NP vec- involved conjugation of AuNPs with specific antibodies which
tor whose lifespan is limited to the therapeutic window of the
drug would be ideal[43]. If the NP vector is cleared from the
system once its purpose is reached, it will reduce exposure
and limit its toxic effects in the body.
Another issue of concern is the penetration rate of AuNPs
into tumors and the specificity of the target sites. Particularly,
the epithelial and endothelial barriers are considered to be the
main hindrance for the NPs to overcome. Penetration enhanc-
ers like metalloproteases against basement membranes and
toxins against intracellular tight junctions, may be useful in
aiding the uptake of drug-loaded AuNPs into the tumor[44].
Another factor to be considered is the AuNP retention in
blood circulation. Some researchers have found that particle
retention is also size-dependent and longer circulation time is
correlated to higher rate of reaching tumor target[45]. In addi-
tion, most studies have only investigated on drug delivery to
solid tumors, where it is site specific and easier for quantifica-
tion of results. It remains to be seen if AuNPs will be effective
against non-solid cancers like leukemia where strategies for
targeting and treating such cancers can be different from that
for solid tumors.
Drug attachment and release from NPs is another challeng-
ing area. While the ease of surface modification is what makes
AuNP attractive for drug delivery, the strength of drug attach-
ment and timing of the release needs to be suitably controlled
to produce the highest therapeutic efficacy. Foremost, the
method of release at the tumor site is dependent on how the
drug is attached to the AuNP, whether covalently or through
non-covalent binding. Generally, drugs in the active form
are loaded non-covalently while the covalent-conjugation of Figure 2. Transmission electron microscopy (TEM) of AuNP treated MCF-7
the drug to AuNP is in the pro-drug form, thereby requiring breast cancer cells. The cells were treated with 1 nmol/L AuNP for 72 h.
a second reaction to release the drug from the attachment as (A) A cluster of AuNPs (indicated by an arrow) is found in the cytoplasm
of a cell. Bar=0.2 µm. (B) TEM specimens were subjected for elemental
well as to activate it. Although there have been quite a num-
analysis with a CM120 BioTWIN electron microscope coupled with a
ber of strategies proposed for the triggering of drug release at
Philips EDAX Microanalysis system. The electron dense particles in AuNP
the tumor site, they can generally be narrowed down to three treated cells showed the presence of two peaks corresponding to the gold
methods: light or photothermal release[46, 47], glutatione-medi- M shell (2.2 KeV) and L shell (9.7 KeV). The treatment sample, registered
ated[48], and non-covalent encapsulation of the active drug a P/B ratio (ratio of the intensity of the detected element against the
with subsequent off-loading by diffusion through the mem- background) of 230.27 (Au L shell). For the element to be significantly
brane[9]. The others are principally a modification of one or present in the sample, the P/B ratio value needs to be 3.0 and above.

Acta Pharmacologica Sinica

 www.chinaphar.com
Lim ZZJ et al
npg
987

functional cytokine which not only plays a critical role in

inflammation and immunity, but also exhibits anticancer
properties[52]. However, its systemic toxicity due to their indis-
criminate actions on both normal and malignant tissues is well
established[16]. Indeed, it was shown in one study using the
mouse model that increasing doses of native TNF correlated
with the severity of toxicities observed[49]. In the same study,
it was revealed that in contrast to native TNF, TNF conjugated
to a colloidal gold platform interspersed with thiol-derivatized
PEG was more efficacious in reducing tumor burden in a colon
cancer xenograft model, without causing death of the animals.
A Phase 1 clinical trial on the PEGylated colloidal gold–TNF
construct (CYT-6091) conducted in patients with advanced
Figure 3. Schematic diagram showing AuNP carriers conjugated with stage solid cancers has shown potential [53]. The CYT-6091
anticancer drugs and ligands which are recognized by receptors on the complex appears to be well-tolerated in this first clinical trial
surface of tumor cells.
on human subjects although fever developed in two patients,
which was not unexpected (as evidenced by preclinical data)
and were easily controlled. It is unclear if the fever was due
bind unique biomarkers expressed on tumor cells [50]. PEG
to a reaction to the AuNPs or the recombinant TNF (rhTNF)
prevented AuNP aggregation and lengthened their retention
construct. It appears that the AuNP and rhTNF construct
time in blood. This facilitated the preferential accumulation
produces less adverse reaction than the rhTNF alone even at
of AuNPs in tumor cells over healthy cells because of the
the highest drug-AuNP concentrations in the pre-clinical find-
elevated permeability of poorly differentiated blood vessels
ings. Dose-limiting toxic reaction of hypotension was also not
around tumors following angiogenesis (Figure 4), as well as
seen in any patient under the trial although there were some
the decreased clearance rate caused by the deficit of functional
retrafficking of leukocytes. AuNPs were found in the tumor
lymphatic vessels in tumors[4]. Using PEG is considered a pas-
as well as in the liver biopsies but no toxic adverse effects
sive targeting approach, as opposed to the active targeting of
were observed. In sum, the authors concluded that the clinical
tumor cells through the help of specific antibodies. Following
results correlated well with the preclinical data, which bodes
cellular uptake, AuNPs are stored in endosomal/lysosomal
well for future translational studies for AuNPs. However, it
vesicles. In order to liberate these AuNPs and introduce the
must be borne in mind that data generated with one type of
drug which has been delivered into the cell cytoplasm, the
AuNP may not be extrapolated to other kinds of AuNPs with
NPs need to be modified by the conjugation of membrane-
a different shape, size or surface modification.
translocating sequence-based peptides which enable them to
In a separate study, the effect of incorporating PEG-coated
traverse monolayers[51].
AuNPs with TNF-α for the targeting killing of SCK mammary
Tumor necrosis factor-alpha (TNF-α) is a potent, multi-
carcinomas grown in mice combined with heat treatment has
also been investigated[54]. While AuNPs loaded with TNF-α
alone and heat treatment alone showed tumor growth delay,
the most drastic effect was observed when TNF-α loaded
AuNPs were intravenously introduced, followed by local
heating. This combination treatment proved effective in
decreasing the in vivo and in vitro tumor cell survival rates,
demonstrating the prospect of using AuNPs as drug delivery
carriers coupled with subsequent thermal treatment for effec-
tive eradication of tumor cells.
The effects of AuNPs conjugated with methotrexate (MTX)
in inducing cytoxicity in vitro and anti-tumorigenic effects in
vivo have been reported[55]. It was observed that accumulation
of Au-MTX in tumor cells occurred more rapidly and at higher
concentrations than those treated with free MTX. As a result,
enhanced cytotoxic effects were also present in several tumor
cell lines compared with an identical dosage of free MTX.
These results warrant further investigation as they suggest
Figure 4. Schematic diagram showing accumulation of ligand-targeted
that the conjugation of AuNPs with a chemotherapeutic drug
gold nanoparticles conjugated with anticancer drugs in cancer cells such as MTX was more efficacious than the administration of
mediated via extravasation of the gold nanocarriers through gaps in the free MTX alone, displaying the potential of AuNPs as drug
endothelial cells (“leaky tumor vasculature”). carriers targeting only tumor cells.

Acta Pharmacologica Sinica

 www.nature.com/aps
npg Lim ZZJ et al
988

However, given the vast array of AuNPs of different shapes and efficient of the two approaches to tumor targeting. It is
and sizes, it is still unclear which type(s) of AuNPs would be apparent from here that plasmonic AuNPs exhibit vast poten-
the most suitable for drug delivery applications[39]. It is likely tial in the field of photothermal cancer therapy by providing a
that this variety of AuNPs will be custom made to suit the means to specifically target tumor cells.
needs for patient treatment. The use of AuNPs in such a man-
ner is not without its disadvantages. There are inherent prob- AuNPs in radiation therapy
lems and potential problems to the use of NPs in the delivery Numerous studies have revealed that AuNPs may have
of drugs to the target site such as size of the NP and drug important applications as radiosensitizers (which are drugs
conjugate, intratumoral pressure and differential expression of that potentiate the effect of radiation for cancer therapy). A
receptors at the tumor site. Optimism towards the utilization study on mice bearing subcutaneous EMT-6 mammary carci-
of AuNPs as drug delivery vectors into cells should be kept in nomas showed that not only were AuNPs (1.9 nm in diameter)
check as many of the complications regarding targeted drug non-toxic in nature and cleared from the body via the kidneys,
delivery as well as the toxicity of NPs to cells is a concern yet they possessed the ability to enhance the effect of X-ray ther-
to be fully addressed. Therefore, the use of AuNPs prior to apy leading to a remarkable survival rate of 86% as opposed
appropriate assessment of their toxic effects may reap more to 20% with X-rays alone and 0% with AuNPs alone[59]. How-
harm than benefit. ever, it is crucial to note that while 1.9 nm AuNPs seem to
show potential as radiation enhancing agents, a recent study
AuNPs in plasmonic photothermal therapy discovered evidence for acute cytotoxicity, DNA damage and
Traditionally, heat has been used in the treatment of cancer apoptosis mediated by oxidative stress induced by cellular
via the induction of hyperthermia, a condition in which cells uptake of 1.9 nm AuNPs[60]. There is a need for further under-
are subjected to high temperatures which kill them. While the standing of cellular responses to AuNPs when exploring their
sources of heat varies from microwaves, radiowaves, ultra- potential to be used in radiation therapy to cure cancer.
sound waves to laser light in the past, such approaches to The effectiveness of AuNPs as radiosensitizers seems to be
cancer therapy have not been widely used because of the con- closely related to their surface functionality. While the above
sequential damage to normal tissues surrounding the targeted studies utilized uncoated AuNPs, another study showed that
tumor. With the advent of nanotechnology, diverse nano- 5 nm AuNPs coated with the gadolinium chelating agent
structures have been manufactured for the purpose of photo- dithiolated diethylenetriaminepentaacetic gadolinium (Au@
thermal therapeutics. Noble metal NPs such as AuNPs (and DTDTPA:Gd) did not exhibit radiosensitizing effect in both
including Au nanospheres, nanorods, and nanocages) attract tumor cells in vitro and in vivo models (MC7-L1 tumor-bearing
particular interest because they possess enhanced absorption mice)[61]. Instead, a chemotherapeutic effect was observed,
cross-sections[50, 56]. Their strong absorbance enables effective which warrants further investigation. The authors suggest
laser therapy with minimal “collateral damage” to the sur- that the radiosensitizing properties of AuNPs could possibly
rounding healthy tissue. The mechanism by which AuNPs be strongly reliant on the nature of their coating. However,
exert their photothermal effect is through SPR. This leads to the discrepancy over the radiosensitizing effects of AuNPs
the formation of a heated electron gas which then cools rap- may also be attributed to the different dimensions of AuNPs
idly within about 1 ps through exchanging energy with the used as well as the type of tumor cells under study.
NP lattice. The NP lattice in turn heats up the surrounding
environment through the rapid transfer of energy spanning AuNPs as antiangiogenic agents
only about 100 ps[57]. The speed at which energy is converted Interestingly, AuNPs have been reported to possess antiangio-
and dissipated to the surrounding environment presents an genic property[62]. The exact mechanism of action is still not
efficient means of rapidly inducing hyperthermia in the vicin- clearly understood but it was observed that AuNPs bind pref-
ity of AuNPs following irradiation with light. Irreversible cell erentially to vascular permeability factor/vascular endothelial
damage resulting from denaturation of proteins and disrup- growth factor (VPF/VEGF)-165 and basic fibroblast growth
tion of cell membrane will occur in the areas subjected to high factor (bFGF) primarily through the heparin-binding domain.
temperatures. This has led researchers to suggest that AuNPs are able to
The underlying concept of using antibody-conjugated inhibit angiogenesis by preventing the downstream signaling
AuNPs hinges on the necessity of tumor cells in express- effects of these mitogens on angiogenesis in cancer cells[63].
ing characteristic biomarkers, which are otherwise absent or
expressed in significantly lower levels in normal cells. The Conclusion
successful detection and eradication of breast carcinoma cells The field of NP research presents exciting potential for bio-
overexpressing human epidermal growth factor receptor 2 medical applications. Together with an expanding knowledge
(HER2) through the usage of anti-HER2 immunotargeted gold base on the properties and effects of AuNPs, they are currently
nanoshells with subsequent irradiation by near infra-red light explored as potential tools for cancer therapy. Presently,
to potentiate the gold nanoshells-induced photothermal effect exploiting AuNPs as sensitive probes in the detection and
has been reported [58]. The antibody-mediated targeting of imaging of tumors for diagnostic purposes, delivery agents
AuNPs to tumor cells was considered to be the more specific for the specific targeting of chemotherapeutic drugs to tumor

Acta Pharmacologica Sinica

 www.chinaphar.com
Lim ZZJ et al
npg
989

cells, and enhancers in plasmonic photothermal therapy and detection of gliomas by chlorotoxin-conjugated superparamagnetic
radiation therapy for the eradication of tumor cells appear to nanoprobes. Small 2008; 4: 372–9.
show promise. In nanomedicine, the ultimate aim is to utilize 16 Powell AC, Paciotti GF, Libutti SK. Colloidal gold: a novel nanoparticle
NPs efficiently for the in vivo targeted killing of tumor cells for targeted cancer therapeutics. Methods Mol Biol 2010; 624: 375–
84.
with no or minimal side effects. However, even the concept of
17 Connor E, Mwamuka J, Gole A, Murphy C, Wyatt M. Gold nanoparticles
attaching ligands to the NPs so as to allow them to hone to the
are taken up by human cells but do not cause acute cytotoxicity.
tumor appears logical and simple but is in fact fraught with Small 2005; 1: 325–7.
difficulties. In this light, NP research is still at its infancy since 18 Shukla R, Bansal V, Chaudhary M, Basu A, Bhonde RR, Sastry M. Bio­
many factors remain to be optimized before the application of compatibility of gold nanoparticles and their endocytotic fate inside
NPs in cancer therapy becomes a clinical reality. the cellular compartment: a microscopic overview. Langmuir 2005;
21: 10644–54.
Acknowledgements 19 Pan Y, Neuss S, Leifert A, Fischler M, Wen F, Simon U, et al. Size-
The authors are grateful to Song-Lin BAY for her assistance in dependent cytotoxicity of gold nanoparticles. Small 2007; 3: 1941–9.
preparing the figures. This work was supported by research 20 Chen YS, Hung YC, Liau I, Huang GS. Assessment of the in vivo
funding from the Singapore Ministry of Education Academic toxicity of gold nanoparticles. Nanoscale Res Lett 2009; 4: 858–64.
21 Johnston H, Hutchison G, Christensen F, Peters S, Hankin S, Stone V.
Research Fund Tier 1 via grant R279-000-205-112 and Tier 2
A review of the in vivo and in vitro toxicity of silver and gold particul­
via grant MOE2008-T2-1-046, and the National University of
ates: particle attributes and biological mechanisms responsible for
Singapore Environmental Research Institute (NERI) via grant the observed toxicity. Crit Rev Toxicol 2010; 40: 328–46.
R706-000-002-646. 22 Chithrani B, Ghazani A, Chan W. Determining the size and shape
dependence of gold nanoparticle uptake into mammalian cells. Nano
References Lett 2006; 6: 662–8.
1 Cancer [homepage on the Internet]. Geneva: World Health Organiza­ 23 Pan Y, Leifert A, Ruau D, Neuss S, Bornemann J, Schmid G, et al. Gold
tion. Accessed Oct 21, 2010. Available from: http://www.who.int/ nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress
cancer/en/. and mitochondrial damage. Small 2009; 5: 2067–76.
2 Wagstaff KM, Jans DA. Nuclear drug delivery to target tumour cells. 24 Li J, Zou L, Hartono D, Ong C, Bay B, Yung L. Gold nanoparticles
Eur J Pharmacol 2009; 625: 174–80. induce oxidative damage in lung fibroblasts in vitro. Adv Mater 2008;
3 Boisselier E, Astruc D. Gold nanoparticles in nanomedicine: prepara­ 20: 138–42.
tions, imaging, diagnostics, therapies and toxicity. Chem Soc Rev 25 Li J, Hartono D, Ong C, Bay B, Yung L. Autophagy and oxidative stress
2009; 38: 1759–82. associated with gold nanoparticles. Biomaterials 2010; 31: 5996–
4 Liu Y, Miyoshi H, Nakamura M. Nanomedicine for drug delivery and 6003.
imaging: a promising avenue for cancer therapy and diagnosis using 26 Tedesco S, Doyle H, Blasco J, Redmond G, Sheehan D. Oxidative
targeted functional nanoparticles. Int J Cancer 2007; 120: 2527–37. stress and toxicity of gold nanoparticles in Mytilus edulis. Aquat
5 Lanone S, Boczkowski J. Biomedical applications and potential health Toxicol 2010; 100: 178–86.
risks of nanomaterials: molecular mechanisms. Curr Mol Med 2006; 27 Browning L, Lee K, Huang T, Nallathamby P, Lowman J, Xu X. Random
6: 651–63. walk of single gold nanoparticles in zebrafish embryos leading to
6 Lewinski N, Colvin V, Drezek R. Cytotoxicity of nanoparticles. Small stochastic toxic effects on embryonic developments. Nanoscale
2008; 4: 26–49. 2009; 1: 138–52.
7 Jain KK. The role of nanobiotechnology in drug discovery. Adv Exp 28 De Jong W, Hagens W, Krystek P, Burger M, Sips A, Geertsma R.
Med Biol 2009; 655: 37–43. Particle size-dependent organ distribution of gold nanoparticles after
8 DeLong RK, Reynolds CM, Malcolm Y, Schaeffer A, Severs T, Wanekaya intravenous administration. Biomaterials 2008; 29: 1912–9.
A. Functionalized gold nanoparticles for the binding, stabiliza­tion, 29 Sonavane G, Tomoda K, Makino K. Biodistribution of colloidal gold
and delivery of therapeutic DNA, RNA, and other biological macro­ nanoparticles after intravenous administration: effect of particle size.
molecules. Nanotechnol Sci Appl 2010; 2010: 53–63. Colloids Surf B Biointerfaces 2008; 66: 274–80.
9 Kim C, Ghosh P, Rotello V. Multimodal drug delivery using gold nano­ 30 Cho W, Cho M, Jeong J, Choi M, Cho H, Han B, et al. Acute toxicity
particles. Nanoscale 2009; 1: 61–7. and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles.
10 Cobley CM, Chen J, Cho EC, Wang LV, Xia Y. Gold nanostructures: a Toxicol Appl Pharmacol 2009; 236: 16–24.
class of multifunctional materials for biomedical applications. Chem 31 Cho W, Kim S, Han B, Son W, Jeong J. Comparison of gene expression
Soc Rev 2011; 40: 44–56. profiles in mice liver following intravenous injection of 4 and 100
11 Zrazhevskiy P, Gao X. Multifunctional quantum dots for personalized nm-sized PEG-coated gold nanoparticles. Toxicol Lett 2009; 191:
medicine. Nano Today 2009; 4: 414–28. 96–102.
12 Biju V, Itoh T, Anas A, Sujith A, Ishikawa M. Semiconductor quantum 32 Kumar S, Harrison N, Richards-Kortum R, Sokolov K. Plasmonic
dots and metal nanoparticles: syntheses, optical properties, and nanosensors for imaging intracellular biomarkers in live cells. Nano
biological applications. Anal Bioanal Chem 2008; 391: 2469–95. Lett 2007; 7: 1338–43.
13 Partha R, Conyers JL. Biomedical applications of functionalized 33 Sperling R, Rivera Gil P, Zhang F, Zanella M, Parak W. Biological
fullerene-based nanomaterials. Int J Nanomedicine 2009; 4: 261– applications of gold nanoparticles. Chem Soc Rev 2008; 37: 1896–
75. 908.
14 Sun C, Lee JS, Zhang M. Magnetic nanoparticles in MR imaging and 34 Roth J. The silver anniversary of gold: 25 years of the colloidal
drug delivery. Adv Drug Deliv Rev 2008; 60: 1252–65. gold marker system for immunocytochemistry and histochemistry.
15 Sun C, Veiseh O, Gunn J, Fang C, Hansen S, Lee D, et al. In vivo MRI Histochem Cell Biol 1996; 106: 1–8.

Acta Pharmacologica Sinica

 www.nature.com/aps
npg Lim ZZJ et al
990

35 Lee S, Chon H, Lee M, Choo J, Shin S, Lee Y, et al. Surface-enhanced delivery. Drug Deliv 2004; 11: 169–83.
Raman scattering imaging of HER2 cancer markers overexpressed 50 Huang X, Jain P, El-Sayed I, El-Sayed M. Plasmonic photothermal
in single MCF7 cells using antibody conjugated hollow gold nano­ therapy (PPTT) using gold nanoparticles. Lasers Med Sci 2008; 23:
spheres. Biosens Bioelectron 2009; 24: 2260–3. 217–28.
36 Kneipp J, Kneipp H, Wittig B, Kneipp K. Novel optical nanosensors for 51 Koch A, Reynolds F, Merkle H, Weissleder R, Josephson L. Transport
probing and imaging live cells. Nanomedicine 2010; 6: 214–26. of surface-modified nanoparticles through cell monolayers. Chem­bio­
37 Kneipp K, Kneipp H, Kneipp J. Surface-enhanced Raman scattering chem 2005; 6: 337–45.
in local optical fields of silver and gold nanoaggregates-from single- 52 van Horssen R, Ten Hagen T, Eggermont A. TNF-alpha in cancer
molecule Raman spectroscopy to ultrasensitive probing in live cells. treatment: molecular insights, antitumor effects, and clinical utility.
Acc Chem Res 2006; 39: 443–50. Oncologist 2006; 11: 397–408.
38 Qian X, Peng X, Ansari D, Yin-Goen Q, Chen G, Shin D, et al. In vivo 53 Libutti SK, Paciotti GF, Byrnes AA, Alexander HR Jr, Gannon WE,
tumor targeting and spectroscopic detection with surface-enhanced Walker M, et al. Phase I and pharmacokinetic studies of CYT-6091, a
Raman nanoparticle tags. Nat Biotechnol 2008; 26: 83–90. novel PEGylated colloidal gold-rhTNF nanomedicine. Clin Cancer Res
39 Cai W, Gao T, Hong H, Sun J. Applications of gold nanoparticles in 2010; 16: 6139–49.
cancer nanotechnology. Nanotechnol Sci Appl 2008; 1: 17–32. 54 Visaria R, Griffin R, Williams B, Ebbini E, Paciotti G, Song C, et al.
40 de la Escosura-Muñiz A, Sánchez-Espinel C, Díaz-Freitas B, González- Enhancement of tumor thermal therapy using gold nanoparticle-
Fernández A, Maltez-da Costa M, Merkoçi A. Rapid identification and assisted tumor necrosis factor-alpha delivery. Mol Cancer Ther 2006;
quantification of tumor cells using an electrocatalytic method based 5: 1014–20.
on gold nanoparticles. Anal Chem 2009; 81: 10268–74. 55 Chen Y, Tsai C, Huang P, Chang M, Cheng P, Chou C, et al. Metho­
41 Lee SH, Bae KH, Kim SH, Lee KR, Park TG. Amine-functionalized trexate conjugated to gold nanoparticles inhibits tumor growth in a
gold nanoparticles as non-cytotoxic and efficient intracellular siRNA syngeneic lung tumor model. Mol Pharm 2007; 4: 713–22.
delivery carriers. Int J Pharm 2008; 364: 94–101. 56 Liu C, Li BQ, Mi CC. Fast transient thermal analysis of gold nano­
42 Duncan B, Kim C, Rotello VM. Gold nanoparticle platforms as drug particles in tissue-like medium. IEEE Trans Nanobioscience 2009; 8:
and biomacromolecule delivery systems. J Control Release 2010; 271–80.
148: 122–7. 57 Link S, El-Sayed MA. Shape and size dependence of radiative, non-
43 De Jong W, Borm P. Drug delivery and nanoparticles: applications radiative and photothermal properties of gold nanocrystals. Int Rev
and hazards. Int J Nanomedicine 2008; 3: 133–49. Phys Chem 2000; 19: 409–53.
44 Sakamoto J, Annapragada A, Decuzzi P, Ferrari M. Antibiological 58 Loo C, Lowery A, Halas N, West J, Drezek R. Immunotargeted nano­
barrier nanovector technology for cancer applications. Expert Opin shells for integrated cancer imaging and therapy. Nano Lett 2005; 5:
Drug Deliv 2007; 4: 359–69. 709–11.
45 Zhang G, Yang Z, Lu W, Zhang R, Huang Q, Tian M, et al. Influence of 59 Hainfeld J, Slatkin D, Smilowitz H. The use of gold nanoparticles to
anchoring ligands and particle size on the colloidal stability and in enhance radiotherapy in mice. Phys Med Biol 2004; 49: N309–15.
vivo biodistribution of polyethylene glycol-coated gold nanoparticles 60 Butterworth KT, Coulter JA, Jain S, Forker J, McMahon SJ, Schettino
in tumor-xenografted mice. Biomaterials 2009; 30: 1928–36. G, et al. Evaluation of cytotoxicity and radiation enhancement using
46 Bikram M, Gobin AM, Whitmire RE, West JL. Temperature-sensitive 1.9 nm gold particles: potential application for cancer therapy. Nano­
hydrogels with SiO 2-Au nanoshells for controlled drug delivery. J technology 2010; 21: 295101.
Control Release 2007; 123: 219–27. 61 Hébert E, Debouttière P, Lepage M, Sanche L, Hunting D. Preferential
47 Agasti SS, Chompoosor A, You CC, Ghosh P, Kim CK, Rotello VM. tumour accumulation of gold nanoparticles, visualised by magnetic
Photo­regulated release of caged anticancer drugs from gold nano­ resonance imaging: Radiosensitisation studies in vivo and in vitro. Int
particles. J Am Chem Soc 2009; 131: 5728–9. J Radiat Biol 2010; 86: 692–700.
48 Hong R, Han G, Fernandez JM, Kim BJ, Forbes NS, Rotello VM. 62 Mukherjee P, Bhattacharya R, Wang P, Wang L, Basu S, Nagy JA, et
Glutathione-mediated delivery and release using monolayer protected al. Antiangiogenic properties of gold nanoparticles. Clin Cancer Res
nano­particle carriers. J Am Chem Soc 2006; 128: 1078–9. 2005; 11: 3530–4.
49 Paciotti GF, Myer L, Weinreich D, Goia D, Pavel N, McLaughlin RE, et 63 Bhattacharya R, Mukherjee P. Biological properties of “naked” metal
al. Colloidal gold: a novel nanoparticle vector for tumor directed drug nanoparticles. Adv Drug Deliv Rev 2008; 60: 1289–306.

Acta Pharmacologica Sinica