Diverse Near-Infrared Resonant Gold Nanostructur - American

Chapter 12

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Diverse Near-Infrared Resonant Gold Nanostructures for Biomedical Applications Jianfeng Huang and Yu Han* Advanced Membranes and Porous Materials Center, Physical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia *E-mail: [email protected].

The ability of near-infrared (NIR) light to penetrate tissues deeply and to target malignant sites with high specificity via precise temporal and spatial control of light illumination makes it useful for diagnosing and treating diseases. Owing to their unique biocompatibility, surface chemistry and optical properties, gold nanostructures offer advantages as in vivo NIR photosensitizers. This chapter describes the recent progress in the varied use of NIR-resonant gold nanostructures for NIR-light-mediated diagnostic and therapeutic applications. We begin by describing the unique biological, chemical and physical properties of gold nanostructures that make them excellent candidates for biomedical applications. From here, we make an account of the basic principles involved in the diagnostic and therapeutic applications where gold nanostructures have set foot. Finally, we review recent developments in the fabrication and use of diverse NIR-resonant gold nanostructures for cancer imaging and cancer therapy.

Introduction In recent years we have seen tremendous advances in modern medical diagnostics and therapeutics. Nevertheless, there exists many opportunities for advancement in early detection and treatment of various diseases (e.g., cancer). Conventional imaging modalities, such as ultrasound imaging (UI), X-ray © 2015 American Chemical Society In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) usually suffer from poor contrast, small dynamic ranges, low sensitivity or low spatiotemporal resolution (1, 2). Meanwhile, the nonspecificity of popular therapeutic strategies, like chemotherapy and radiotherapy, bring many pernicious side effects. In addition, theranostic (diagnostic and therapeutic) agents, such as Gd3+ for MRI enhancement, radiolabeled molecules or chemotherapy drugs are often limited by short blood circulation time and biodistribution (3). Consequently, it is imperative to develop improved theranostic strategies for simpler and more effective treatments. In recent years, the appealing biological, chemical and physical properties of gold nanostructures are causing them to emerge as an important class of theranostic agents for biomedical applications including imaging, therapy and drug delivery (4). Biologically, they exhibit exceptional cell compatibility, without significant adverse effects on cell viability and function (e.g., proliferation and differentiation) due to the inherent low cytotoxicity of elemental gold (5, 6). Chemically, they are stable and readily functionalized via surface modifications for either passive or active targeting to selective sites, which enhances specificity and thus, effectively eliminates or mitigates nonspecific damage to surrounding healthy tissues (7). In addition, a number of state-of-the-art synthetic methods have been developed that offer precise control over their physicochemical parameters (e.g., size, shape and aggregation state). Physically, gold nanostructures possess rich and intriguing optical properties arising from an excitation of localized surface plasmon resonance (LSPR). LSPR is an electromagnetic resonance under which conduction electrons oscillate collectively with the incident light at the interface between metallic nanostructures and their surrounding dielectric media (Figure 1a) (8). Reflected in the extinction spectrum, there are one or more peaks positioned at different wavelengths, depending on the size, shape, composition, the surrounding medium, etc. For example, for Au nanospheres, there is generally one LSPR band at around 525 nm. Upon such a resonance, gold nanostructures can effectively trap the incident light and render an intense electromagnetic field in the vicinity of the particle surface at the resonant wavelength. Optical applications, such as surface-enhanced Raman scattering (SERS) and surface-enhanced fluorescence (SEF), benefit greatly from the enhanced electromagnetic field (9). Following LSPR excitation, localized surface plasmons decay on the timescale of femtoseconds, either radiatively through resonant light scattering or nonradiatively via creation of hot electrons (Figure 1b) (10). While scattered light can be used for nanoparticle-enhanced optical bioimaging, the generated hot electrons can either be captured by external species, for example, molecular oxygen to generate reactive oxygen species (ROS) for photodynamic therapy (11), or be cooled down through electron–phonon collisions at a time scale of 1−100 ps (12), ultimately leading to a rise in the lattice temperature. Thereafter, the thermal energy dissipates into the surroundings, which plays an essential role in broad biomedical applications, such as photoacoustic imaging, photothermal therapy and light-controlled drug release. In the case of non-radiative decay, either intraband excitations within the conduction band or interband excitations between other bands (e.g., d-bands) and the conduction band may take place. For noble-metal nanostructures, interband 214 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


excitations also account for luminescence that can be used for fluorescence imaging. Figure 1b summarizes localized surface-plasmon decay routes and their potential biomedical applications.

Figure 1. Excitation and decay of localized surface plasmons. (a) Schematic of plasmon oscillation for a metal sphere. (b) Schematic representation of radiative and nonradiative decay of localized surface plasmons in noble-metal nanoparticles and their potential biomedical applications. e−—electron, h+— electron hole, ROS—reactive oxygen species, PDT—photodynamic therapy, PTT—photothermal therapy, PAI—photoacoustic imaging and LCR—light-controlled release.

To harness the unique optical properties of gold nanostructures for in vivo applications, it is critically important to tailor the LSPR band into biological optical windows I (650–900 nm) and II (1000–1350 nm), where light attenuation, including absorption and scattering, from oxygenated blood, deoxygenated blood, skin and fatty tissue is lowest (Figure 2) (13, 14). Gold nanostructures present themselves as an extremely attractive nanomedical agent for exploiting this spectral regime, because their LSPR can be finely adjusted by changing their size, shape composition and aggregation states. This broad degree of tuning makes gold nanostructures resonant in near infrared (NIR) conditions, and thus very useful for various clinical diagnostic and therapeutic applications. By the same token, NIR resonant among miscellaneous gold nanostructures will be discussed in this chapter, with particular emphasis on their up-to-date biomedical applications.

Biomedical Applications: Imaging and Therapy This section briefly discusses the underlying physical principles of the imaging and therapy modalities for which Au nanostructures are exploited. Imaging applications include scattering- and luminescence-based optical imaging, surface-enhanced spectroscopy-based imaging, and photoacoustic imaging. Therapeutic applications include photodynamic therapy, photothermal therapy, drug delivery and light-controlled drug release. 215 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 2. Optical windows in biological tissues. These plots of effective attenuation coefficient (on a log scale) versus wavelength show that absorption and scattering from oxygenated blood, deoxygenated blood, skin and fatty tissue is lowest in either the first or second near-infrared window. Reproduced with permission from reference (13). Copyright 2009 Nature Publishing Group.

Scattering- and Luminescence-Based Optical Imaging When LSPR in Au nanostructures undergoes a radiative decay, strong light scattering occurs at the LSPR frequency. Under optical microscopy, the scattered light is collected, and the location of the Au nanostructures can be imaged. Serving as imaging contrast agents, gold nanostructures that are accumulated in specific cells via either passive or active targeting enable the differentiation of target cells from surrounding cells. Two optical techniques, reflectance confocal microscopy (15) and optical coherence tomography (16) have been widely used. Moreover, gold nanostructures have been found to generate luminescence (17). Single-photon luminescence is identified as a three-step process: (i) creation of electron-hole pairs via one-photon excitation of electrons from the d-band to the sp-band, (ii) scattering of the excited electrons and holes by phonons with partial energy transferred and (iii) recombination of electron–hole resulting in photon emission (18). Two-photon luminescence is considered to follow a similar mechanism, with the exception of two sequential one-photon absorption events in the first step (19, 20). Two-photon luminescence is relatively weak, but can be greatly intensified by the strong electric field produced during LSPR. For elemental Au, as the d-sp band transition takes place below ~600 nm, two-photon luminescence excited by NIR light and amplified by NIR-resonant Au nanostructures is particularly desirable for biomedical imaging. Compared with fluorescent probes used in optical image, gold nanostructures do not suffer from 216 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

photobleaching or photoblinking, thus encouraging their wide use as contrast agents for light-scattering or two-photon luminescence bioimaging.


Surface-Enhanced Spectroscopy-Based Imaging The term surface-enhanced spectroscopy generally encompasses surfaceenhanced Raman scattering (SERS) and surface-enhanced florescence (SEF). When probes, such as characteristic biomolecules of cells, tissues or biomarkers, are situated in the vicinity of Au nanostructures, their “fingerprint” Raman signals can be greatly amplified by the strong electric field resulting from the LSPR (21). In addition, NIR light can be reliably exploited, as Raman shifts are excitation wavelength independent. Thanks to these merits, SERS has become a powerful technique for in vivo detection and imaging applications (vide infra). In SEF, the fluorescence enhancement is jointly attributed to an enhanced absorption of fluorophores by the strong electric field, an improved radiative decay rate of fluorophores (for example, owing to the localized density of photonic states of plasmonic nanocrystals), and an increased emission via coupling of the fluorescence emission to the far field (3). Unlike in SERS, however, the fluorophores in SEF should not be in close proximity to the Au nanostructure’s surface (< ~4 nm). Otherwise, fluorescence will be significantly quenched due to the damping of molecular oscillators by electron tunneling/transfer between the metal and the fluorophore, and/or the fluorophore’s own field which is reflected by the metal and out of phase with the directly emitted field of the fluorophore (22). SEF with optimally placed fluorophores near the surface of Au nanostructures has been widely employed for in vitro and in vivo imaging. Photoacoustic Imaging (PAI) Photoacoustic imaging (PAI), also known as optoacoustic imaging, combines light (typically NIR) and ultrasound to produce an image with a greater spatial resolution than ultrasound techniques and deeper depth profiles than purely optical techniques. Briefly, when short laser pulses are absorbed and then dissipated to local heats, a rapid thermoelastic expansion of surrounding tissues will take place, leading to the generation of an ultrasound wave. The ultrasound wave is then collected and converted to electric signals with a transducer and finally processed to produce an image. The photoacoustic effect can be approximated by a simplified equation (23):

Where, P is the pressure rise of the generated acoustic wave, Γ is the Grueneisen parameter, µa is the absorption coefficient, F is the laser fluence, β is the thermal coefficient of volume expansion, c is the speed of sound and Cp is the heat capacity at constant pressure. From this equation, it is evident that the PA signal is directly related to temperature, as both β and c in the Grueneisen parameter are positively correlated with temperature. Au nanostructures, capable 217 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

of effectively absorbing and transforming light energy into thermal energy at the LSPR frequency, have been widely applied as contrast agents for this imaging modality.


Photodynamic Therapy (PDT) Photodynamic therapy (PDT), also known as photochemotherapy, involves cell death induced by reactive oxygen species (ROS, e.g., singlet oxygen 1O2, superoxide radical anion •O2ˉ and hydroxyl radical •OH) through the destruction of cellular components (e.g., DNA, RNA and proteins). ROS are generally produced as a consequence of energy or electron transport in photochemical and photobiological processes that are initiated by the reaction of organic photosensitizer chromophores with tissue oxygen under the irradiation of a specific wavelength of light. PDT is particularly promising for its site-specific treatment and dark non-toxicity (24). A major drawback of PDT is caused by the long retention of photosensitizer drugs in the body, which renders the patient highly sensitive to light (7). In addition, many organic photosensitizers have their excitations in the UV-visible range, limiting their in vivo applications for deep-tissue-buried tumors. Moreover, common photosensitizers, such as porphyrins and phthalocyanines, are often too hydrophobic to be used without chemical modifications, which poses considerable challenges for targeting them in tumor sites (25). In recent years, a series of inorganic nanomaterials have also been proven capable of generating ROS under irradiation including typical semiconductor nanomaterials (TiO2, quantum dots) (26, 27) and carbon nanomaterials (nanotubes, C60) (28, 29). In particular, some studies found that 1O2 can be produced from noble-metal nanostructures through an energy transfer mode when they are illuminated with a continuous wave (CW) or pulsed laser source (30–32). During Au nanoparticle (AuNP) irradiation, two pathways of 1O2 production have been proposed: a plasmon-activated pathway via interactions of plasmons and hot electrons with molecular oxygen, and an indirect photothermal pathway that induces extreme heat development leading to particle fragmentation and thermionic electron emission (30). The later pathway is more pronounced in the case of AuNP irradiation with pulsed laser sources. The role that Au nanostructures play in PDT is generally considered as either a carrier for organic molecular photosensitizers or on their own as inorganic photosensitizers. Photothermal Therapy (PTT) Photothermal therapy (PTT) generally refers to a hyperthermic treatment, including low-temperature hyperthermia (41-45 °C) and high-temperature thermal ablation (46-56 °C), which uses light as the heating source to damage abnormal cells. Hyperthermic effects range from the induction of cell apoptosis by denaturalizing intracellular proteins that are related to cellular survival and proliferation to cell destruction and tissue ablation via direct cell necrosis (33, 34). The necrotic destruction of cancer cells involving high temperatures usually 218 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


causes collateral damage to healthy cells and undesirably reshapes nanostructures (34). Because cancer tissues do not have a sufficient blood supply and vascular structures to dissipate heat, they have a lower temperature tolerance limit than do healthy tissues; therefore, they can be selectively damaged at temperatures between 41 and 45 °C (35). For less invasive cancer cell death, it is therefore advantageous to use a low-temperature-based (41-45 °C) PTT strategy. Au nanostructures hold particular promise as PTT-photosensitizers due to their large photon absorption and efficient photothermal conversion at LSPR. Drug Delivery and Light-Controlled Drug Release Many clinically used drugs are either highly hydrophobic or low molecularweight compounds that diffuse readily into healthy tissues. As a consequence, little if any of the drug reaches the target sites (36). It is essential to improve the region-specific delivery and release of drugs that can greatly increase the efficacy of therapies. A promising strategy is to use Au nanostructures as a “nanocarrier” to transport drugs to target sites and then liberate them under light irradiation. Compared to conventional drug delivery systems, Au nanostructures serving as a delivery vehicle have at least three advantages: decreased biodegradation of drugs, improved solubility of hydrophobic drugs and reduced immunogenicity (37). In particular, instead of a direct use for hyperthermal killing of malignant cells, the heat generated from the photothermal conversion of Au nanostructures can be harnessed to spatially and temporally control drug release. Currently, three major photothermo-responsive drug release schemes have been reported (38): breakage of polymer or liposome structures where drugs are encapsulated, rupture of a linker molecule through which drugs are tethered to the Au nanostructures via a covalent bond, and diffusion of drugs from thermosensitive hydrogels, silica matrices or polymers.

Diverse NIR-Resonant Gold Nanostructures Although gold nanoparticles have a long history of applications in clinical treatments, the use of NIR-responsive gold nanostructures only began this century. To date, a variety of NIR-resonant gold nanostructures have been developed and thoroughly explored as either imaging or therapy agents. Most recently, research on these structures has shifted to the design and application of their integration with other materials to construct a versatile platform that can accommodate multiple theranostic modalities within a single nanoscale complex. The currently available NIR-resonant gold nanostructures can be roughly categorized into five classes: Au Nanorods, Au Nanoprisms, and Au Nanoplates These three structures feature an anisotropic shape as opposed to the isotropic shape of spherical AuNPs (Figure 3). Reduced symmetry means that these structures possess more than one surface SPR band. In particular, one well-defined band can be tuned into the NIR range via changing the size parameter. For 219 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


example, Au nanorods (AuNRs) exhibit two SPR bands, one weak transverse band in the visible range (~520 nm) and another strong longitudinal band in the NIR range, provided that the aspect ratio (the ratio of length to diameter) is larger than ~3.5 (41). Seed-mediated growth is the most exploited method for preparing AuNRs (42, 43); this involves the addition of citrate-capped Au nanoparticle seeds into a growth solution containing the Au precursor (HAuCl4) and a reducing agent (ascorbic acid) together with cetrimonium bromide and Ag+. The aspect ratio can be finely controlled by varying the ratio of seed to Au precursors as well as the time delay between synthesizing steps (44). For Au nanoplates and nanoprisms, the in-plane modes dominate the spectra while out-of-plane excitations are only important for small, thick nanoprisms (45). In-plane modes can be tuned into NIR via changing the ratio of the edge length to the thickness. To date, the pioneering solution-phase light-mediated syntheses and various thermal techniques are reliable for producing nanoprisms/nanoplates with a high yield (46). A commonality shared by most of these syntheses is mediated reduction of metal ions onto pre-synthesized nanoparticle seeds with twin planes. Therefore, all experimental details influencing either the crystallographic structure of the seeds or the redox chemistry of the second step can have a drastic effect on the final structures and thus on the LSPR bands.

Figure 3. (a, c) Transmission electron microscopy (TEM) images of (a) Au nanorods and (c) Au nanoprisms. (b) Scanning electron microscopy (SEM) image of Au nanoplates. Figure 3b adapted with permission from reference (39). Copyright 2005 American Chemical Society. Figure 3c adapted with permission from reference (40). Copyright 2008 American Chemical Society.

The ease of large-scale and high-yield synthesis together with the superior optical properties of AuNRs have made them one of the most exploited NIRresonant gold nanostructures for various biomedical applications as discussed in Section 2. Recent research efforts are improving the previous theranostic modality and developing more effective thermo-chemotherapy (47). Some progress toward these directions is highlighted below. Signal generation by metal nanostructures during PAI mainly relies on the conversion of light to heat, the transfer of the heat to the environment and the 220 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


resultant production of pressure transients. Previous focus has primarily been on the conversation of light to heat by developing efficient light-to-heat conversion structures. Recently, it was demonstrated that improvements to the heat transfer process can strongly amplify photoacoustic (PA) performance. For example, Emelianov et al. reported that silica-coated AuNRs could produce three-fold higher PA signals than uncoated AuNRs of the same optical density (48). The results of a series of control experiments suggested that the enhancement was caused by a reduction in the interfacial thermal resistance between AuNRs and the surrounding solvent as a consequence of the silica coating. Lim et al. found that PA performance could be further improved through coating AuNRs with reduced graphene oxide (RGO) (49). Simulations found that the electromagnetic fields of the AuNR@RGO were 1.5 and 4 times stronger than those of the AuNR@SiO2 and bare AuNRs, respectively. Moreover, AuNR@RGO also showed a heat transfer rate 2.5 and 10 times higher than the AuNR@SiO2 and bare AuNRs, respectively, due to the excellent thermal conductivity of RGOs. Thus, these results revealed that the RGO coating contributed to both light absorption and heat transfer, improving PA performance. A challenge to PTT lies in adequately heating an entire tumor mass, while avoiding unnecessary collateral damage to the surrounding healthy tissue. Recently, Berlin et al. (50) identified an innovative method to improve the intratumoral distribution of AuNRs, thereby increasing the efficacy of PTT by conjugating tumor-tropic neural stem cells (NSCs) with AuNRs. Results show that after loading AuNRs, NSCs were unimpaired in their viability, yet they retained AuNRs long enough to migrate throughout tumors. In a mouse model, intratumoral injections of Au nanorod-loaded NSCs were more efficacious than free Au nanorod injections, as evidenced by a reduced recurrence rate of triple-negative breast cancer (MDA-MB-231) xenografts following NIR exposure. This work highlights the advantage of combining cellular therapies and nanotechnology to generate more effective cancer treatments. Meanwhile, previous reports were largely based on organic photosensitizermediated PDT, usually in combination with AuNR-mediated PTT to achieve synergistic PTT and PDT effects to kill cancer cells. Xu et al. (51) recently demonstrated that owing to their large two-photon absorption cross-sections, AuNRs can effectively generate ROS singlet oxygen (¹O2) under two-photon excitation, which is significantly higher than traditional organic photosensitizers such as Rose Bengal and Indocyanine Green. Guided by AuNRs’ two-photon fluorescence imaging, the two-photon PDT effect was demonstrated on HeLa cells in vitro. Hwang et al. (52) later demonstrated that AuNRs alone can sensitize the formation of ROS ¹O2 and exert PDT effects on the destruction of mice tumors under very low LED/laser doses of single-photon NIR excitation (915 nm, < 130 mW/cm²). They found that AuNR-mediated phototherapeutic effects could be switched from PDT to PTT or a combination of both, depending on the NIR light excitation wavelengths. In particular, in vivo mice experiments revealed that the PDT effect via irradiation of AuNRs from 915 nm could destroy the B16F0 melanoma tumor in mice far more effectively than chemotherapy using the anticancer drug doxorubicin (DOX) and PTT under 780 nm light irradiation. 221 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 4. DNA assembly of a targeted, NIR-responsive delivery platform and disassembly under NIR irradiation. Reproduced with permission from reference (53). Copyright 2012 John Wiley and Sons. In the field of light-induced drug delivery, targeting is always important for theranostic agents to reduce side effects induced by a lack of specificity. Farokhzad et al. (53) designed a targeted NIR light-responsive delivery platform through DNA self-assembly. As shown in Figure 4, the platform comprises three functional components: complementary DNA strands, the AuNR and a polyethylene glycol (PEG) layer. The DNA strands provide loading sites for doxorubicin (DOX) via the intercalation of DOX with the strands’ GC base pairs. In addition, one of the two strands is thiolated for AuNR capture, and the other is pre-conjugated with ligands for cell-specific targeting. AuNRs serve as the NIR light-to-heat transducer for PTT and for disassembling the DNA double strands under NIR irradiation, which leads to the triggered release of loaded drugs at target chemotherapy sites. The PEG layer facilitates the nanoparticles to evade recognition by the immune system and prolongs the circulation of the nanoparticles. Both in vitro and in vivo results demonstrated that this platform selectively delivered DOX to target cells, released them upon NIR irradiation and effectively inhibited tumor growth through thermo-chemotherapy. One limitation of this study lies in the local delivery strategy of intratumoral injection, which cannot provide as rich biodistribution information of the particles as does intravenous injection; for example, Qian et al. (54) co-loaded AuNRs and DOX in polymersomes (P-AuNRs-DOX) to facilitate co-therapy of photothermal and chemotherapies. Under NIR, laser irradiation induced local hyperthermic heating of AuNRs such that polymersomes were corrupted and released DOX. Ablation of tumor cells in vitro and in vivo showed that co-therapy offered significantly improved therapeutic efficacy over chemotherapy or PPT alone. However, biodistribution analysis after intravenous injection showed that AuNRs accumulated primarily in reticuloendothelial systems (RES) with a tumor uptake of 7.94 % ID/g at 24 h, implying that further efforts could be devoted to improve 222 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


targeting (e.g., by conjugation with tumor cell surface receptor-ligands). Chen et al. (55) developed a novel NIR laser-induced anticancer targeting strategy with facile control and practical efficacy, but without using active targeting ligands (Figure 5). It involved AuNR-PNIPAM nanocomposites that contain AuNRs encapsulated in a thermoresponsive polymer, poly (N-isopropylacrylamide) (PNIPAM). This polymer undergoes a reversible phase transition in aqueous solution from an extended hydrophilic chain to a condensed hydrophobic globule when the temperature rises above 32 °C. As reduced size favored extravasation of nanocomposites from the pore-enlarged vasculature system to the tumor tissue at elevated temperatures, when the tumor (mouse murine 4T1 breast tumor on the right hind leg) was irradiated with a NIR laser (760 nm) for 20 min immediately after the intravenous administration of the nanocomposites, a significantly enhanced accumulation (7.6-fold) of nanocomposites was observed in the tumor. This enhanced accumulation of nanocomposites provided a prerequisite for their effective therapeutic application. For example, it further induced sufficient temperature increase for PTT due to the photothermal conversion of AuNRs under NIR irradiation. Moreover, when they were loaded with the anticancer drug DOX, effective heat-induced release of doxorubicin to the tumor was realized. This thermo-chemotherapy almost completely inhibited tumor growth and lung metastasis.

Figure 5. NIR laser-induced targeted thermo-chemotherapy using the Au nanorod-PNIPAM nanocomposites. Reproduced with permission from reference (55). Copyright 2014 American Chemical Society.

Although to a lesser extent than AuNRs, Au nanoplates/nanoprisms have also been explored for biomedical applications. For example, Okamoto et al. (56) demonstrated that triangular nanoplates could be used as two-photon-induced photoluminescence imaging agents for cell imaging. When Au nanoplates were conjugated to yeast cells which were either dead in air or alive in water, a visible two-photon excited luminescence could be detected by two-photon laser scanning microscopy using an NIR 810 nm laser as an excitation. Cui et al. (57) used Au nanoprisms as signal amplifiers in multispectral optoacoustic tomography 223 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


to visualize gastrointestinal cancer. Au nanoprisms were first PEGylated to increase their biocompatibility then injected into mice for the visualization of tumor angiogenesis in gastrointestinal cancer cells. The results demonstrated the capacity of PEGylated Au nanoprisms to penetrate tumors and provide a high-resolution signal amplifier for optoacoustic imaging. Tortiglione et al. (58) explored photothermal cell ablation by using Au nanoprisms in an invertebrate model organism. Living polyps (Hydra vulgaris) were first treated with Au nanoprisms and then NIR irradiated. The results showed that Au nanoprisms could be well internalized into living specimens, with no sign of toxicity. Moreover, they induced efficient cell ablation throughout the body and the overexpression of the hsp70 gene under NIR irradiation. The results showed that different cells/tissues responded differently, initiating either necrosis or a defense response. Therefore, this work not only demonstrated that gold nanoprisms could be employed as efficient heat mediators in model organisms, but also suggested NIR-triggered cell ablation as a tool to study cell function. In addition to their application for singular imaging or therapy techniques, Au nanoplates have also been demonstrated to be able to perform multiple functionalities as theranostic agents. In a recent study by Zhen et al. (59), Au nanoplates synthesized via an epitaxial growth of Au on palladium nanosheets and then modified with SH-PEG, were found to be an effective multifunctional platform for both PA and CT imaging and photothermal cancer therapy. The PEGylated Au nanoplates showed a rather high accumulation in the tumor site after an intravenous injection. Besides the enhanced permeability and retention (EPR) effect due to the tortuous and leaky nature of tumor vasculature and the surface PEGylation prolonged circulation time in the blood, the unique two-dimensional (2D) structural feature of the nanoplates was believed to be another critical contributing factor to such high accumulation in tumors. Moreover, obvious enhancement of CT value and four-fold enhanced PA signals after 24 h injection of the PEGylated Au nanoplates were observed. Imaging-guided PTT was also achieved using an 808-nm laser with a low power density of 0.5 W/cm2, much lower than that for most reported photothermal agents. These results thus, demonstrated the superiority of 2D nanostructures for in vivo biomedical applications. Au Nanostars, Au Nanopopcorns, Au Nanoflowers, Au Nanoechinus Protruding tips from a solid core geometrically characterize these four structures. Depending on the sharpness (length divided by width), the tips are roughly classified as branches, bumps, petals or spikes (Figure 6). The plasmonic modes of these structures arise from the hybridization of the individual plasmons from the core and the tips. The tips localize the low-energy plasmon mode at their apexes, which results in an LSPR band in the NIR region (60, 64). Synthesis of these structures typically involves kinetically controlled growth of polycrystalline gold nanoparticle seeds. Under the fast reduction rate, preferential growth occurs along certain crystalline facets of the starting seeds and thus, multiple tips form on solid cores. The molar ratio of the Au precursors to the seed is a crucial factor in determining the morphology and tip plasmon resonance wavelength (65). 224 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 6. (a, d) SEM images of (a) Au nanostars and (d) Au nanoechinus. (b, c) TEM images of (b) Au nanopopcorns and (c) Au nanoflowers. Figure 6a adapted with permission from reference (60). Copyright 2006 American Chemical Society. Figure 6b adapted with permission from reference (61). Copyright 2010 American Chemical Society. Figure 6c adapted with permission from reference (62). Copyright 2014 the Royal Society of Chemistry. Figure 6d adapted with permission from reference (63). Copyright 2014 John Wiley and Sons.

Through appropriate surface modifications, these structures have found wide biomedical applications. Lu et al. (66) demonstrated that Au nanostars, when modified with amine-terminated (positively charged in acidic condition) and carboxyl-terminated (negatively charged in basic condition) polyethylene glycol (PEG), could be endowed with a sensitive response in cellular uptake and PTT efficacy to the extracellular pH (pHe) gradient between normal tissues and tumors (Figure 7). Specifically, by optimizing the composition ratio of amine-/carboxyl-terminated PEG to be 4, the resulting structure (GNS-N/C 4) exhibited high cell affinity and therapeutic efficacy at pH 6.4 for Hela cells, but low affinity and almost “zero” damage to cells at pH 7.4. Mice models with an intravenous injection of GNS-N/C 4 further revealed that a significantly increased tumor accumulation and complete ablation of orthotopic breast cancer xenograft under NIR-laser (808 nm) irradiation. 225 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


226 Figure 7. Schematic illustration of the preparation of PEGylated mixed-charge Au nanostars (GNSs) and their pH-reversible cell affinity and photothermal therapeutic efficacy. Reproduced with permission from reference (66). Copyright 2015 John Wiley and Sons.

In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Ray et al. (61) reported that the modification of Au nanopopcorns with Rh6G-labeled aptamers and an anti-PSMA antibody for targeted diagnosis, nanotherapy treatment and in situ monitoring of the PTT response of prostate cancer LNCaP cells using SERS. Since the PSMA level in cancer cells is usually much higher than in normal tissues, the anti-PSMA antibody conjugated Au nanopopcorns would selectively accumulate and then aggregate on the prostate cancer LNCaP cells. Once aggregated, these Au nanopopcorn aggregates exhibit an extremely high SERS intensity for probe molecule Rh6G-modified aptamers (Enhancement Factor: 2.5 × 109) due to the formation of hot spots inside aggregates. Meanwhile, localized heating of PTT under NIR irradiation caused irreparable cellular damage to the prostate cancer cells. After PTT, breakage of Rh6G-labeled aptamers from morphologically changed Au nanopopcorns resulted in a greatly reduced SERS signal. Therefore, an in situ time-dependent SERS assay could be used to monitor the photothermal-nanotherapy response during the therapy process. Xu et al. (67) functionalized Au nanoflowers with folic acid for targeting the human hepatocellular carcinoma cancer cell line (HepG2) and 4-mercptopyridine as a Raman probe. By taking advantage of the intraparticle hot-spot-induced superior SERS performance of individual Au nanoflowers (Enhancement Factor: ~2.1 × 108), they managed to perform in vitro SERS imaging of living cells. Provided that an appropriate coating was exerted on the Au nanoflowers as a spacer, such superior intraparticle hot spot property of Au nanoflowers can also be used for enhancing the fluorescence efficiency of quantum dots (QDs). In a recent study by Zhu et al. (62), Au nanoflower@SiO2@CdTe/CdS/ZnS (QD) composite structures were synthesized. After linking them with antibody (AT) molecules, the resultant Au nanoflower@SiO2@QD-AT composites well targeted the membrane of MCF-7 and MDA-MB-231 breast cancer cells. As a result, due to the enhanced local electric field and the large absorption cross section of Au nanoflowers, an enhanced florescence emission was observed from the cancer cells and an efficient PTT-induced cancer cell death was found under NIR-laser irradiation. Au nanoechinus was only fabricated most recently by Hwang et al. (63) A Au nanoechinus has an average particle size of ~350 nm and many well-defined tips protruding from the particle surface (aspect ratio: ~ 9). An intriguing property of this structure is that it exhibits an extended NIR absorption of up to 1700 nm, which covers both the NIR-I (650–950 nm) and NIR-II biological windows (1000–1300 nm). The extinction coefficients, ~ 0.69 × 1012 M−1cm−1 at 915 nm (NIR I) and 0.74 × 1012 M−1cm−1 at 1064 nm (NIR II), are the largest values ever reported for nanomaterial, which are 7-9 orders and 3-4 orders higher than those of conventional organic dyes and gold nanoparticles, respectively. Impressively, this structure was demonstrated to be able to sensitize the formation of ROS 1O2. After coating with lipid molecules, resultant lipid-coated Au nanoechinus performed effectively in vivo PDT and PTT in both the first- and the second-NIR biological windows for complete destruction of tumors in mice. Upon 915-nm (NIR I) and 1064-nm (NIR II) light exposure, cellular deaths were mainly induced by PDT, while PTT contributed around one-fifth and one-fourth for 915 nm and 1064 nm, respectively. This structure represents the first example where gold 227 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

nanostructures work as dual modal PDT and PTT reagents for the complete destruction of mice tumors in both the first and the second biological windows.


Au Nanocages, Au Hollow Nanospheres, Au Nanotubes, Au Nanorod-in-Shell This set of nanostructures is all produced via a galvanic replacement reaction between HAuCl4 and sacrificial Ag nanoparticles with a certain shape, although in the case of Au hollow nanospheres, Co nanoparticles are more commonly used than their Ag counterparts. Specifically, the sacrificial nanoparticles employed for these four structures are Ag nanocube (68, 72), Co nanosphere (69, 73), Ag nanorod (70), and Ag-coated Au nanorod (71). The resultant nanostructures generally still maintain their overall geometric shapes, but a hollow interior with porous walls or shells are newly formed (Figure 8). The SPR bands of these structures undergo a considerable bathochromic shift relative to the original sacrificial templates, and can be readily tuned into NIR by tuning the inner size, outer wall thickness and the ratio of Au to Ag (68).

Figure 8. (a) SEM image of Au nanocages. (b-d) TEM images of (b) Au hollow nanospheres, (c) Au nanotubes, and (d) Au nanorod-in-shell. Figure 8a adapted with permission from reference (68). Copyright 2004 American Chemical Society. Figure 8b adapted with permission from reference (69). Copyright 2014 American Chemical Society. Figure 8c adapted with permission from reference (70). Copyright 2015 John Wiley and Sons. Figure 8d adapted with permission from reference (71). Copyright 2013 American Chemical Society. 228 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Au nanocages (AuNCs) with hollow interiors and tunable SPR peaks in the NIR region have been used recently for orthogonally triggered release by choosing the right laser according to the AuNCs’ SPR. In a study by Qu et al. (74), two types of AuNCs were prepared with two different LSPRs and preloaded with two types of effectors in the hollow interiors before being covered with a smart polymer shell (Figure 9). When exposed to a laser beam with a wavelength matching the absorption peak of the AuNCs, this polymer collapsed due to the high local temperature, thus exposing the pores on the nanocages and thereby releasing the pre-loaded effectors. When the laser was turned off, the polymer chains would relax back to the extended conformation and terminate the release. As a result, when enzyme and substrate were chosen as the two effectors and selectively released from two different AuNCs, enzymatic reactions between enzyme and substrate occurred only after the successful opening of both types of AuNC capsules. The system acts as an “AND” logic gate. However, when the AuNCs are preloaded with isoenzyme or enzyme inhibitor, an “OR” or “INHIBIT” logic gate operation is established. This study represents a good example of NIR light-encoded, logically controlled, intracellular release systems. AuNCs were also used as a nanocarrier for a PDT molecular photosensitizer. Pandey et al. (75) demonstrated that when conjugated with a PDT photosensitizer, AuNCs enabled dual image-guided delivery of the photosensitizer and significantly improved the efficacy of PDT in a murine model. The photosensitizer, 3-devinyl-3-(1’-hexyloxyethyl)pyropheophorbide (HPPH), was non-covalently entrapped in a poly(ethylene glycol) monolayer that was coated on the surface of AuNCs. Such entrapped HPPH can be delivered more effectively to the tumor as compared to free HPPH. In addition, the presence of the AuNCs enhanced the 1O2 generation and the phototoxicity of the HPPH in vitro. As a result, the growth of the tumor in vivo was suppressed due to the combination of the effective delivery and the enhanced phototoxicity of the AuNC-HPPH conjugates. In the meanwhile, fluorescence and photoacoustic imaging provided information aiding the monitoring of the progression of delivery and tumor treatment following PDT. AuNCs themselves can directly work as a PDT photosensitizer. They were selected as representative plasmonic metal nanostructures, owing to their strong one-/two-photon absorption in the NIR region, to study the relevant mechanism of photo-induced tumor cell death, which involved hyperthermia and PDT effects. In a recent study by Gao et al. (76), NIR-light-excited hot electrons were found to generate either ROS (including 1O2, •O2ˉ, •OH) or hyperthermia (Figure 10). Compared with one-photon irradiation, two-photon irradiation brought about much more ROS. In addition, in vitro experiments disclosed that ROS-triggered mitochondrial depolarization and caspase protein up-regulation, which resulted in tumor cell apoptosis under two-photon irradiation, while hyperthermia mainly induced tumor cell necrosis. These findings suggest a regulation of plasmon-mediated ROS and hyperthermia for optimized anticancer phototherapy. Despite being a promising phototherapy agent, AuNCs have a short blood circulation lifetime, which limits their tumor uptake and thus in vivo applications. This limitation was overcome recently by cloaking AuNCs with red blood cell (RBC) membranes that act as a natural stealth coating. Yang et al. (77) found that while the fusion of RBC membranes over AuNCs preserved the unique 229 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


porous and hollow structures of AuNCs, the resulting RBC-membrane coated AuNCs (RBC-AuNCs) were further rendered good colloidal stability. NIR laser irradiation experiments demonstrated that the RBC-AuNCs possessed in vitro photothermal effects and selectively ablated cancerous cells as did the pristine biopolymer-stealth-coated AuNCs, but they further exhibited greatly enhanced in vivo blood retention and circulation lifetime in a mouse model. As a result, tumor uptake of RBC-AuNCs increased, and mice that received PTT cancer treatment modulated by RBC-AuNCs achieved a 100% survival rate over 45 days. These results show that applying a stealth coating is effective in prolonging circulating RBC-AuNCs for in vivo applications and thus improves PTT efficacy.

Figure 9. Schematic representation of a NIR light-encoded logic gate for controlled release based on the AuNC copolymer. Adapted with permission from reference (74). Copyright 2014 John Wiley and Sons.

In a recent study by Drezek et al. (78), a novel magnetic hollow Au nanosphere complex that incorporates iron oxide nanoparticles (IONPs) in the hollow interior was designed. This complex was synthesized by conjugating IONPs (~10 nm) onto silver cores (~35 nm) using 3mercaptopropyltrimethoxysilane (MPTMS) followed by a second layer of silver enwrapping the IONPs. After gold salt was added, a thin gold layer was formed while etching away the silver in a similar fashion to traditional hollow Au nanospheres. Compared to previous hollow Au nanospheres or Au nanoshell structures, two advantages of this complex are obvious. First, multiple IONPs were incorporated in this way, improving the overall magnetic properties, and thus the particle’s capability as a MRI contrast agent. Second, the resultant complexes are ~60 nm, which is optimal for cellular retention and tumor accumulation of nanoparticles, while a plasmonic peak was still maintained in the NIR range (~800 nm). As a result, the complexes performed well as MRI T2 contrast agents and also debulked tumors and improved survival with effective PTT. 230 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 10. Schematic illustration of AuNCs as intrinsic inorganic photosensitizers mediating the generation of ROS (1O2, •O2ˉ, •OH) and hyperthermia under NIR one-/two-photon irradiation. Depending on the irradiation power intensity, AuNC-PEG-mediated phototherapy could effectively affect tumor cells by two different pathways. ROS played a leading role in apoptosis at low power, and hyperthermia mainly resulted in necrosis at high power. Reproduced with permission from reference (76). Copyright 2014 American Chemical Society.

Evans et al. reported the first in vitro and in vivo study of gold nanotubes (AuNTs) most recently (70). The sacrificial Ag nanorods were 300–700 nm long with ~50nm diameters. These resultant Au NTs with ~6 nm-thick walls showed strong LSPR absorption in the NIR region that could be tuned by varying the length of the starting AgNRs or by adjusting the Au precursor to Ag nanorod ratio. After being functionalized with poly (sodium 4-styrenesulfonate) (PSS), the PSS-AuNTs possessed high colloid stability and low cytotoxicity, and could be internalized by cancer cells (SW480 cells) and macrophages (RAW 264.7) as revealed by the in vitro dark-field optical imaging. In vivo experiments showed that PSS–Au NTs accumulated at the SW620 tumor site but had a hepatobiliary clearance within 72 h. In addition, the AuNTs rendered excellent photoacoustic signals and photothermal ablation performance. Unlike the nanotube structures fabricated from pure Ag nanorods, the AuNR-in-shell structure synthesized using Ag-coated Au nanorods as a sacrificial substrate were responsive to both the first and second NIR windows, despite their small dimensions below 100 nm (71). Specifically, the structure (length: ~53 nm, 231 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


width: ~26 nm) containing an Au NR (length: ~40 nm, width: ~10 nm) in a cavity of a AuAg nanoshell showed an intriguing attribute, i.e., a broad absorbance band across 300–1350 nm with two NIR SPR bands located at approximately 1100 and 1280 nm. Very few, if any, nano-sized light absorbers in the second NIR region were reported prior to this work. With this nanostructure, the first in vitro and in vivo photothermal cancer therapy in the second NIR window was demonstrated. Using a continuous wave of 808 nm (first NIR window) or a 1064 nm (second NIR window) diode laser, large cell-damaged area beyond the laser-irradiated area was observed, indicating a high efficacy of the NIR photothermal destruction of cancer cells.

Au Nanoshells The Au nanoshell (AuNS) nanostructure, first generated by Halas’ group, is comprised of a dielectric silica core surrounded by an ultrathin gold shell (SiO2@AuNSs) (79). Its synthesis includes an attachment of Au seeds (~2 nm) on SiO2 spheres followed by an iterated growth of gold layers until a continuous shell with a desired thickness is formed (Figure 11). The plasmon hybridization between the shell’s inner and outer surfaces dictates the SPR properties of this structure. By varying the core size and shell thickness, a single SPR band can be generated in the NIR window. This SiO2@AuNS is sometimes referred to as the first generation of AuNSs. Since its invention, a variety of the so-called the second generation of AuNSs structures, including magnetic-cored AuNSs (e.g., Fe3O4@AuNSs and FePt@AuNSs) (80–82), polymer-cored AuNSs (e.g., poly (lactic-co-glycolic acid, PLGA@AuNSs) (83), quantum dot-cored AuNSs (e.g., CdSe/ZnS@AuNSs) (84), and liposome-cored AuNSs (e.g., poly-L-histidine@AuNSs) (85), have been synthesized by replacing the SiO2 core with other materials.

Figure 11. TEM images showing the formation of SiO2@AuNSs via iterated growth of gold layers on Au seeds attached SiO2 sphere. Adapted with permission from reference (79). Copyright 1999 American Institute of Physics. 232 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Recent studies on AuNSs have been extensively focused on the development of a multi-modality image-guided theranostic platform. For example, gadolinium was conjugated to SiO2@AuNSs for multimodal diagnostic imaging and photothermal cancer therapy. West et al. (86) found that after conjugating gadolinium, the resulting conjugates were rather versatile in affording contrast enhancement for a wide range of diagnostic modalities, including MRI, X-ray, optical coherence tomography, reflectance confocal microscopy, and two-photon luminescence, with resolutions spanning anatomic to sub-cellular length scales, thus facilitating the application in image-guided PTT enabled by AuNSs. Melancon et al. (87) reported the fabrication of super-paramagnetic iron-oxide-containing AuNSs (SPIO@AuNSs), which are capable of simultaneous photoacoustic (PA) and magnetic-resonance- (MR) guided photothermal ablation (PTA) therapy. Because of the intrinsically high near-infrared optical absorbance and strong magnetic property of SPIO@AuNSs, in vivo dual-modality PA-MR imaging-guided monitoring of therapeutic effects after PTT for mouse tumors have been demonstrated. In addition, a much clearer structure of the tumor blood vasculature was visualized using the PA technique after an intravenous administration of SPIO@AuNSs. Dai et al. (88) developed an AuNS-based multifunctional theranostic nanoparticle (DOX@PLA@AuNS-PEG-MnP) by growing AuNSs around poly(lactic acid) (PLA) nanoparticles encapsulating DOX, followed by tethering a Mn-porphyrin derivative (MnP) on the AuNS surface through the linker molecule polyethylene glycol (PEG). The biodegradable PLA served as a drug carrier, while AuNSs worked as the NIR photo absorber to perform PTT and trigger instant drug release. PEG prolonged the circulation time in vivo, whereas a Mn-porphyrin derivative effectively enhanced the MRI contrast. As a result, a greatly improved longitudinal relaxivity was realized, as demonstrated in both in vitro and in vivo experiments, which provided accurate information regarding the location and detailed structure of the tumor through MRI. Under the irradiation of an NIR laser, the combined light-triggered release of DOX and photothermal treatment was more cytotoxic than either treatment alone in both cellular experiments and tumor-bearing nude mice models.

Au Nanoparticle Ensembles The aforementioned four families of NIR-responsive gold nanostructures were all developed within a single particle’s regime. Their NIR absorption arises either from particular shape-induced plasmon mode or from coupling between plasmon modes within the particle. A novel type of NIR-active nanostructures (Au nanoparticle ensembles) was also designed in recent years, based on the aggregation/assembly of a collection of individual AuNPs (Figure 12). The NIR–responsive property originates from the aggregation/assembly induced interparticle plasmon coupling, and thus can be delicately tailored by controlling the properties (e.g., size and shape) of the individual building particles. Currently, two common strategies have been developed to achieve such nanoparticle ensembles: pH-induced aggregation (89, 91–95) and amphiphilicity-driven self-assembly (90, 96, 97). 233 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 12. (a) TEM images showing pH-induced aggregation of individual gold nanoparticles (top) into aggregates (bottom). (b) SEM image of plasmonic gold nanovesicles self-assembled from Au nanoparticles. Figure 12a adapted with permission from reference (89). Copyright 2009 American Chemical Society. Figure 12b adapted with permission from reference (90). Copyright 2013 American Chemical Society.

Kim et al. (89) pioneered the use of pH to induce the aggregation of small AuNPs (~10 nm) into larger aggregates for PTT. They functionalized the AuNPs with a “smart” surface molecule citraconic amide. This molecule is negatively charged and stable in neutral or basic conditions, but it hydrolyzes to a positively charged protonated amine at a pH < 7.0. When AuNPs are internalized into the mildly acid intracellular environment of a cancerous cell, hydrolysis of the citraconic amide rendered nanoparticle surfaces with mixed charges, which resulted in an aggregation of small AuNPs via electrostatic interactions. The aggregates accumulated because their increased sizes caused the block of exocytosis. In particular, the absorption of the initial AuNPs in the visible range shifted to the far-red and NIR spectra. This absorption shift was then exploited for in vitro photothermal cancer therapy with a 660 nm laser. Using B16 F10 mouse melanoma, NIH 3T3 mouse embryonic fibroblast cells, and HeLa cells, the photothermal efficacy of aggregates was greatly improved compared to those of two control groups using citrate capped AuNPs and without using any AuNPs. 234 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 13. Schematic illustration of the working mechanism of “smart” AuNP-DOX conjugates. AuNP-DOX conjugates consist of AuNPs modified with smart surface ligands and covalently conjugated DOX. The AuNP-DOX releases DOX by pH-triggered linker cleavage under the mild acidic conditions typical of a tumor. Simultaneously, AuNP-DOX converts the surface charge from negative to a mixture of negative and positive charges, which induces a rapid aggregation among the nanoparticles via electrostatic interactions. This spatiotemporally concerted release from AuNP-DOX was exploited for chemo- and photothermal combination cancer therapy. SANDC—Smart Au Nanoparticles-Dox Conjugates. Adapted with permission from reference (94). Copyright 2014 American Chemical Society.

Based on a similar principle, other pH-sensitive bifunctional platforms that combine PTT and chemo-therapy (94) or PTT and SERS imaging (95) were developed by functionalizing the small AuNPs with the anticancer drug DOX or Raman probes, respectively. For example, they grafted DOX to the terminals of 235 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


the smart surface molecule citraconic amide via a carbodiimide coupling between the –NH2 group of DOX and the terminal –COOH group of citraconic amide (Figure 13). Again, when the individual small AuNPs with surfaces functionalized with both citraconic amide and citraconic amide-doxorubicin conjugates, were internalized into cancerous cells, the acidic intracellular environment induced not only an aggregation of small particles, but a release of doxorubicins due to hydrolysis of the carbodiimide bond. Such a doubly pH-responsive (aggregation and DOX release) therapy system showed nearly an order of magnitude enhanced cytotoxicity in vitro when compared with two sequential independent treatments. The advantage of this synergistic effect was also confirmed by an in vivo animal model, where a significant suppression of tumor growth and no noticeable damage to other organs were detected. In the case of SERS imaging, 4-mercaptobenzoic acid was introduced to the AuNP surface as a Raman probe. The pH-induced aggregation of AuNPs provided hot spots for SERS with the enhancement factor reaching 1.3 × 104, thus enabling a concomitant SERS imaging in addition to PTT. In addition to irregular macroscopic aggregates, self-assembly of plasmonic nanoparticles into more well-defined, discrete ensembles has also been developed for biomedical applications. Duan et al. (96) developed plasmonic vesicles assembled from SERS-active amphiphilic AuNRs for cancer-targeted drug delivery that allowed for simultaneous SERS detection and synergistic chemo-PTT of specific cancer cells (Figure 14). To synthesize the SERS-active amphiphilic AuNRs, they coated initially cetrimonium bromide (CTAB)-stabilized AuNRs with a Raman probe 2-naphthalenethiol (NPT) and mixed polymer brushes of hydrophilic poly (ethylene glycol) (PEG) and hydrophobic polylactide (PLA). After that, the plasmonic vesicle was generated by self-assembly of the amphiphilic Au nanorods via a film rehydration method. The interparticle plasmonic coupling of the resultant plasmonic vesicles provided a large electric field for SERS detection and induced a significant red-shift of the SPR band into the NIR range; for example, 808 nm. In addition, the plasmonic vesicle offered a hydrophobic PLA shell and large aqueous cavity for loading of anticancer drugs. In this way, plasmonic vesicles were shown to be capable of specifically targeting EpCAM-positive cancer cells, leading to ultrasensitive spectroscopic detection of cancer cells. Moreover, the combination of the photothermal effect of AuNRs and the large loading capacity of the vesicles showed higher efficiency in killing targeted cancer cells than either single therapeutic modality, due to the localized synergistic PTT and photothermal-triggered chemotherapy. Finally, LSPR peaks have been engineered to the NIR region by self-assembly of spherical AuNPs. For example, Nie et al. (97) reported a dialysis-guided assembly of amphiphilic block copolymer, poly (ethylene glycol)-b-poly (e-caprolactone) (PEG-b-PCL), tethered AuNPs (~26 nm) into Au nanovesicles (AuNVs) in a THF/water system (Figure 15). The resultant AuNVs exhibited broad extinction spectra with major peaks positioned in the NIR range and tunable by changing the initial AuNP concentration. The strong NIR absorption and high photothermal conversion efficiency (~ 37%) enabled simultaneous PAI and enhanced PTT efficacy. Moreover, after the completion of PTT, the AuNVs dissociated into discrete AuNPs, which improved particle clearance. 236 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 14. Schematic illustration of the synthesis of SERS-active amphiphilic AuNRs (AuNR@NPT/PEG/PLA) with Raman probes NPT and mixed polymer brushes PEG and PLA, and self-assembly of AuNR@NPT/PEG/PLA into plasmonic vesicles (Top). The plasmonic vesicles exhibited a unique combination of SERS, PTT, and laser-induced drug release (Bottom). Adapted with permission from reference (96). Copyright 2013 American Chemical Society.

The advantage of the hollow interior space of the vesicles could further be taken to load active compounds for constructing a multifunctional theranostic platform. For example, when photosensitizer Ce6 molecules were encapsulated in the plasmonic vesicles, a unique trimodality NIR fluorescence/thermal/photoacoustic imaging-guided synergistic PTT/PDT with improved efficacy was demonstrated by the same group (90). The AuNVs that were prepared by rehydration-triggered self-assembly of polyethylene oxide-b-polystyrene (PEO-b-PS)-tethered AuNPs had a strong absorbance in the NIR range of 650–800 nm, as a result of the plasmonic coupling between neighboring AuNPs in the vesicular membranes. This enabled the use of 671-nm laser irradiation to simultaneously excite AuNVs to generate heat for PTT and 237 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Ce6 to produce ROS for PDT, killing cancer cells. Meanwhile, the efficacy of such a treatment could be monitored by visualizing the tumor tissues with the aid of the fluorescence, thermal and PA signals arising from AuNVs-Ce6 in tumor cells. Both in vitro and in vivo results showed that the therapeutic efficacy of AuNVs-Ce6 was enhanced compared to either PTT or PDT alone, or even the sum of PTT/PDT, indicating a synergistic effect. These results, together with other advantages, such as high Ce6 loading efficiency (~18.4 wt. %) and enhanced Ce6 delivery into cells, make AuNVs-Ce6 a potential theranostic platform for imaging-guided synergistic PTT/PDT of tumors in vivo.

Figure 15. Self-assembly of biodegradable Au vesicles composed of poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL)-tethered AuNPs through the dot–line–plane–vesicle mode during the dialysis process. Au vesicles with an ultrastrong plasmonic coupling effect were superior PAI and PTT agents with improved clearance after the dissociation of the assemblies. The PA signal and PTT efficiency of Au vesicles increased as the distance (d) between adjacent AuNPs decreased. GNP—Au nanoparticles. Reproduced with permission from reference (97). Copyright 2013 John Wiley and Sons. 238 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Summary and Outlook The inherent properties of gold nanostructures, such as their good biocompatibility, ease of surface functionalization and shape-dependent LSPR, make them well suited as NIR photosensitizers in biomedical applications. We describe how a variety of recent advances use NIR-resonant gold nanostructures (nanorods, nanoprisms, nanoplates, nanostars, nanoflowers, nanoechinus, nanopopcorns, nanocages, hollow nanospheres, nanotubes, nanorod-in-shell, nanoshells and nanoparticle ensembles) for efficient imaging (scattering- and luminescence-based optical imaging, surface-enhanced spectroscopy-based imaging and photoacoustic imaging) and therapeutic (photodynamic therapy, photothermal therapy, drug delivery and light-controlled release) agents for in vitro and in vivo theranostic applications. Despite their great potentials, some contradictions associated with the in vivo toxicity and theranostic efficacy of gold nanostructures in a complex body environment need to be well compromised before they can be translated to clinical practice. (i) Shape features such as corners, tips, edges and pores are essential structural origins of the intriguing LSPR properties of NIR-resonant gold nanostructures. However, in many cases these features have small dimensions (e.g., < 5 nm) and/or are enclosed with high-index facets. As a result, although gold nanoparticles larger than 5 nm are generally inert and considered to be nontoxic and biocompatible, gold nanostructures may be more reactive than bulk gold and thus present certain toxicity. (ii) Surface modifications represent a good strategy to improve the colloidal stability and blood circulation time or to increase the accumulation in target sites, thus enhancing theranostic efficacy. Nevertheless, surface ligands introduced for these specific functionalities (e.g., colloidal stability and targeting) may either directly impart the gold cores with toxicity (for example, the toxicity of CTAB-stabilized AuNRs was found to stem from CTAB) or polarize the gold cores into a more reactive oxidation state (for example, a Au-S bond induces Auδ+-Sδ-). (iii) It appears that gold nanostructures in size of 10-100 nm are ideal because they are small enough to have sufficient diffusion in the extracellular space and resistance to the phagocyte system but also large enough to avoid being rapidly cleared during circulation through extravasation or renal clearance. Currently, some of the gold nanostructures described in this chapter (e.g., nanoechinus, nanotubes, nanoshells and nanoparticle ensembles) are much larger than 100 nm, which could affect their uptake and thus limit the full exploitation of their theranostic potentials. In addition, these structures are too big to be efficiently eliminated from the body, for example via renal clearance, and they would, therefore, redistribute and pose chronic hazards to other healthy tissues or organs. Ideal NIR-resonant gold nanostructure-based theranostic agents for clinical applications should possess strong NIR-responsivity, low inherent toxicity, good site-specific targeting ability and effective clearance from the body after use.

239 In Recent Progress in Colloid and Surface Chemistry with Biological Applications; Wang, Chengshan, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

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