Gold nanoparticle-mediated photothermal therapy: applications
and opportunities for multimodal cancer treatment
Rachel S. Riley
1
and Emily S. Day
1,2,*
1
Department of Biomedical Engineering, University of Delaware, Newark, DE, USA
2
Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
Abstract
Photothermal therapy (PTT), in which nanoparticles embedded within tumors generate heat in
response to exogenously applied laser light, has been well documented as an independent strategy
for highly selective cancer treatment. Gold-based nanoparticles are the main mediators of PTT
because they offer: (1) biocompatibility, (2) small diameters that enable tumor penetration upon
systemic delivery, (3) simple gold-thiol bioconjugation chemistry for the attachment of desired
molecules, (4) efficient light-to-heat conversion, and (5) the ability to be tuned to absorb near-
infrared light, which penetrates tissue more deeply than other wavelengths of light. In addition to
acting as a standalone therapy, gold nanoparticle-mediated PTT has recently been evaluated in
combination with other therapies, such as chemotherapy, gene regulation, and immunotherapy, for
enhanced anti-tumor effects. When delivered independently, the therapeutic success of molecular
agents is hindered by premature degradation, insufficient tumor delivery, and off-target toxicity.
PTT can overcome these limitations by enhancing tumor- or cell-specific delivery of these agents
or by sensitizing cancer cells to these additional therapies. All together, these benefits can enhance
the therapeutic success of both PTT and the secondary treatment while lowering the required doses
of the individual agents, leading to fewer off-target effects. Given the benefits of combining gold
nanoparticle-mediated PTT with other treatment strategies, many exciting opportunities for
multimodal cancer treatment are emerging that will ultimately lead to improved patient outcomes.
INTRODUCTION
Nanoparticle-mediated PTT has been rapidly developing as a standalone therapy for cancer
because it enables selective hyperthermia of tumor tissue while avoiding damage to healthy
tissue. In PTT, plasmonic nanoparticles (NPs) are delivered into tumors and are irradiated
with laser light, which causes the NPs’ conduction band electrons to undergo synchronized
oscillations that result in either the absorption or scattering of the applied light.
1
The
absorbed light is converted into heat, which irreversibly damages the surrounding diseased
tissue (Figure 1(a)). While NPs made of various materials can be employed for PTT,
2–4
gold-based nanoparticles (AuNPs), which we define here as those consisting either entirely
or partially of gold (such as silica core/gold shell ‘nanoshells’), have emerged as the lead
*
Correspondence to: emilyday@udel.edu.
Conflict of interest: The authors have declared no conflicts of interest for this article.
HHS Public Access
Author manuscript
Wiley Interdiscip Rev Nanomed Nanobiotechnol
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2018 July 01.
Published in final edited form as:
Wiley Interdiscip Rev Nanomed Nanobiotechnol
. 2017 July ; 9(4): . doi:10.1002/wnan.1449.
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therapeutic platform because they offer several major benefits. First, AuNPs enable simple
gold-thiol bioconjugation chemistry for surface functionalization with therapeutic
molecules, targeting ligands, or passivating agents that enhance biocompatibility as
described in detail below. Additionally, the optical properties of AuNPs” can be tuned by
controlling their structural dimensions so that they maximally absorb near-infrared (NIR)
light (λ ≈ 650–1350 nm), which is ideal for PTT because it can safely penetrate deeply
through healthy tissue to reach AuNPs embedded within tumors. A third benefit of AuNPs is
that they can passively accumulate within tumors
via
the enhanced permeability and
retention (EPR) effect, which exploits the inherently leaky and unorganized tumor
vasculature.
5
Because of these benefits, AuNP-mediated PTT has been thoroughly
investigated for tumor ablation in animal models and has even entered clinical trials.
1,6–9
However, PTT as a standalone treatment is limited because it does not affect metastatic
lesions or tumor cells outside of the area of irradiation, both of which may lead to disease
recurrence. To overcome these limitations and enhance treatment outcome, researchers have
recently begun to explore the use of AuNP-mediated PTT in combination with secondary
therapeutic approaches that take advantage of the physiological and cellular changes within
tumors afforded by PTT. Additionally, they have begun to utilize optical imaging techniques
to guide and assess treatment in real-time. In this review, we first discuss the design features
of AuNPs that are ideal for photothermal applications and then describe how PTT aids in the
success of supplemental therapies. We also highlight the use of imaging to guide PTT.
Finally, we discuss opportunities and challenges for the use of AuNP-mediated PTT in
multimodal strategies for cancer management.
Design of Gold Nanoparticles for Photothermal Therapy
AuNPs used in photothermal applications must meet several design criteria such as having
plasmon resonance tunability, high photothermal conversion efficiency,
13,14
and simple
surface functionalization or encapsulation chemistry. Based on these design criteria,
nanoshells (NSs), nanorods (NRs), nanocages (NCs), and nanostars have emerged as the
most common photothermal transducers. Here, we use these formulations as examples to
discuss the desirable properties of AuNPs for PTT as depicted in Figure 1(b). This section is
not meant to be a comprehensive overview, as others have discussed this topic elsewhere,
1,15
but we highlight key features that researchers should consider as they plan to use PTT in
individual or multimodal therapeutic strategies.
First, AuNPs used in PTT must be designed to absorb light within the first (650–850 nm) or
second (950–1350 nm) NIR window because these wavelengths of light can safely and
deeply penetrate healthy tissue to reach AuNPs embedded within tumors. An important
feature of AuNPs is that their structural dimensions can be tuned to yield maximal
absorption within one of these two regions of light. The majority of AuNPs have been
designed to maximally absorb within the first NIR window, which can safely penetrate 2–3
cm of tissue. For example, the peak plasmon resonance of NSs, which consist of spherical
silica cores with thin gold shells, can be tuned by adjusting their core diameter-to-shell
thickness ratio. NSs with 120 nm diameter cores and 15 nm thick shells are typically used
for PTT because they maximally absorb 800 nm light.
16,17
Likewise, NRs have a short and
long axis, thereby offering two absorption peaks corresponding to the transverse (λ ≈ 500–
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550 nm) and longitudinal (λ ≈ 650–850 nm) surface plasmon resonance (SPR).
18,19
The rod
length can be shortened or elongated to achieve peak longitudinal SPR in the NIR region.
10
NRs on the order of 10 nm × ×40 nm maximally absorb ~800 nm light and are therefore the
most common for PTT. While most AuNPs have been designed to maximally absorb within
the first NIR window, more recently novel AuNP designs have emerged for PTT in the
second NIR window. This is because these longer wavelengths can safely penetrate up to 10
cm of tissue to reach deeply embedded tumors.
20–22
For example, Tchounwou et al.
demonstrated the use of AuNP-coated single-walled carbon nanotubes as a multifunctional
platform for imaging and PTT within the second NIR window.
22
Although we expect that
PTT utilizing second window NIR light will gain attention in the coming years, here we
focus on PTT within the first NIR window because it has been more commonly studied in
combination PTT applications.
In addition to absorbing NIR light, AuNPs intended for use in PTT should also display high
photothermal conversion efficiency, which is dictated by the AuNPs’ structural dimensions
(i.e., size and shape). The photothermal conversion efficiency of AuNPs of different sizes
and shapes, and how this measurement can be determined, has been extensively studied in
literature, and we point the reader towards these published works for more in-depth
discussion.
13,15,23,24
In general, for spherical AuNPs, those with smaller diameters have
higher conversion efficiency than those with larger diameters. Additionally, non-spherical
AuNP designs, including NRs, nanostars, and NCs, are more efficient photothermal
transducers than their spherical counterparts like NSs due to their larger absorption cross
sections.
15,19
Notably, the size and shape of AuNPs also influence their ability to extravasate from
vasculature and penetrate solid tumors, which will ultimately impact the success of PTT
because it will influence how evenly heat is distributed throughout the tumor.
25,26
For
example, Perrault et al. compared the tumor penetrating abilities of 20 nm, 60 nm, and 100
nm solid gold spheres and found that larger size limits the distance NPs can travel away
from blood vessels and into tumors.
26
However, tumor retention of smaller AuNPs is
challenging because they are rapidly cleared from the extracellular milieu. Therefore, it is
critical to determine the optimal size for penetration
and
retention based on the tumor
characteristics (i.e., the ‘leakiness’ of its vasculature, the organization of its lymphatic
vessels, and the density of the tumor extracellular matrix). This is particularly important
given that the EPR effect is now known to be heterogeneous in distinct tumor types.
27
Intriguingly, PTT can be used to overcome these tumor penetration and retention limitations
by amplifying tumor vessel leakiness and extracellular matrix permeability to enhance the
delivery of more AuNPs or secondary therapeutic molecules, which we discuss later in this
review.
28,29
Another important consideration for AuNP design is their ability to encapsulate or be
functionalized with biomolecules or drugs to enable combination therapy. The gold exterior
of AuNPs is beneficial for bioconjugation because it enables simple gold-thiol bonding. One
advantage of anisotropic materials like nanostars, which are spiked AuNPs, is that they offer
a high surface-to-volume ratio for bioconjugation.
30
This can be advantageous because
loading density can influence how AuNPs interact with cells and tissues. One disadvantage
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of loading molecules on the exterior of solid AuNPs, however, is that it leaves them
susceptible to immune recognition or degradation. Hollow, porous AuNPs, such as NCs,
offer the ability to load therapeutic agents in the nanoparticle core.
11
Since most hollow
AuNPs destabilize upon NIR irradiation, the release of encapsulated molecules can be
triggered ‘on demand.’
31
Although this photothermal reshaping is desirable for drug
delivery, it causes the AuNPs to lose their peak SPR to preclude their repeated use for PTT.
Using NRs, researchers have demonstrated that one way to counteract this reshaping upon
irradiation is by coating the NPs with a silica shell.
32
A similar strategy could be employed
for other AuNPs that are known to reshape upon irradiation.
Here, we focused on how AuNPs’ size, shape, and surface modifications can influence their
heat generation and tumor penetration. In addition, these features also impact the AuNPs’
biodistribution and biocompatibility, as demonstrated in various cell and animal
models.
12,33–35
Similar to bulk gold, AuNPs are generally considered to be chemically inert
and biocompatible.
35
However, upon intravenous administration, AuNPs are rapidly coated
with serum proteins that alter their biological identity and change how they are presented to
cells.
36–38
Further, AuNPs are quickly recognized by the mononuclear phagocytic system,
also known as the reticuloendothelial system (RES), leading to their rapid clearance from the
blood. AuNPs’ surface coating largely dictates the formation of the protein corona and
clearance from the body. To reduce non-specific protein adsorption, extend circulation time,
and enhance biocompatibility, AuNPs are often coated with passivating agents, such as
poly(ethylene) glycol (PEG), in addition to targeting agents or other therapeutic molecules.
The length and density of PEG on AuNPs is important, as it influences how well the AuNPs
are shielded from protein corona formation and clearance from the body.
37
Among the
various types of AuNPs used for PTT, NSs coated with PEG (also known as AuroShells,
which are being commercialized by Nanospectra Biosciences, Inc.) are the furthest along in
development and are currently the only AuNP for PTT being evaluated in clinical trials.
These trials are examining the safety and efficacy of nanoshell-mediated PTT against lung,
head and neck, and prostate cancers.
7–9
The first publication regarding these human trials
indicates that PEG-coated NSs have an excellent clinical safety profile,
39
supporting their
continued use and providing evidence that PEG is a viable surface coating for AuNPs
intended for human PTT. Although there are several clinical trials ongoing, efficacy data
from these trials has not yet been published. In the
Opportunities and Challenges
section of
this review, we further discuss ongoing clinical applications of AuNPs for PTT.
Overall, there are many features that contribute to whether a specific AuNP design will work
well for PTT, and we have highlighted a few here. As previously mentioned, investigators
have begun studying PTT in combination with other therapeutic strategies for overall
enhanced therapeutic efficacy by exploiting the physiological and cellular level effects of
PTT in tumors as described in the next section.
Physiological Effects of PTT and the Mechanism of Cell Death Induced by PTT
AuNP-mediated PTT causes several physiological and biological changes to the surrounding
tumor environment that can maximize the cytotoxic effects of PTT itself, enhance the
efficacy of secondary therapies, or decrease required treatment dosages for secondary
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agents.
40–42
For example, the heat generated by AuNPs can increase the permeability of
tumor vessels and cancer cell membranes to increase tumor and cellular uptake, respectively,
of additional AuNPs or drugs (Figure 2(a)). We highlight some of the benefits of
combination strategies that exploit these effects of PTT later in this review.
In addition to increasing tumor vessel and cell membrane permeability, PTT also causes
intracellular effects such as DNA damage and protein denaturation. Recently, researchers
have begun to study the mechanisms of cell death triggered by PTT more closely because
the mechanism of cell death (i.e., necrosis versus apoptosis) activates different cell signaling
pathways that may influence treatment success and be beneficial for potential combination
therapeutic strategies (Figure 2(b)). Conventional PTT uses high energy irradiation to cause
rapid nanoparticle heating leading to cellular necrosis; while this strategy is effective for the
ablation of established tumors,
16,17,43
it can also induce undesirable effects. For example,
high energy PTT resulting in cellular necrosis can trigger the release of cellular waste and
damage-associated molecular patterns (DAMPs) that induce inflammation, which may lead
to increased secondary tumor growths.
44,45
Conversely, low energy PTT initiates cellular
apoptosis, which may lead to beneficial immunogenic responses.
44,45
For example, cellular
apoptosis can potentially discourage inflammation by causing phagocytes to produce anti-
inflammatory molecules such as TGF-β.
46
Further, macrophages and dendritic cells (DCs)
enter an anti-inflammatory state when in contact with apoptotic cells. The ability to induce
apoptosis versus necrosis with PTT depends on many factors, including the AuNP
photothermal properties, AuNP concentration in diseased tissue, and irradiation conditions.
Given that initiating apoptosis versus necrosis with PTT can result in very distinct cellular
effects, researchers should carefully control PTT parameters for their particular application.
In addition, investigators should consider utilizing PTT in combination with secondary
treatment strategies to capitalize on the tissue- or cellular- level effects induced by PTT.
Below, we review how the physiological changes and mechanisms of cell death induced by
PTT can be combined with chemotherapy, gene regulation, and immunotherapy for
synergistic approaches to cancer treatment. We then describe how imaging can be used to
guide and assess PTT in real-time.
ENHANCING CHEMOTHERAPY WITH GOLD NANOPARTICLE-MEDIATED
PHOTOTHERMAL THERAPY
Although mortalities due to many cancers have not significantly improved in the past few
decades, chemotherapy remains the current standard-of-care treatment. While cytotoxic at
high doses, chemotherapy success is often hindered by acquired drug resistance and adverse
side effects that limit the maximum administered dose. As previously mentioned,
hyperthermia increases both vascular and cell membrane permeability, as well as
extracellular matrix permeability.
28
These physiological changes can amplify the effect of
subsequently applied chemotherapy by increasing intratumoral and intracellular drug
content.
42,47
Further, drug cytotoxicity may be enhanced by heat application.
48
One of the
early indications of the synergy between hyperthermia and chemotherapy was demonstrated
by Hahn et al., who showed optimal cytotoxicity by co-treating cells with doxorubicin and
heat at 43°C.
49
The clinical feasibility of widespread hyperthermia, however, is limited
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