Gold Nanocages: A Novel Class of Multifunctional Nanomaterials for Theranostic Applications

Abstract

Gold nanocages represent a novel class of nanostructures, well-suited for biomedical applications. They can be readily prepared via the galvanic replacement reaction between silver nanocubes and chloroauric acid. Their optical resonance peaks can be easily and precisely tuned to the near-infrared region from 650-900 nm, the transparent window for blood and soft tissue. Furthermore, their surface can be conveniently conjugated with various ligands for targeting cancer. In this feature article, we highlight recent advances in the large-scale synthesis of gold nanocages and their applications in cancer diagnosis and treatment. Specifically, we have scaled up the production of gold nanocages for in vivo studies and evaluated their tumor targeting capabilities. We have also demonstrated their use as contrast agents for photoacoustic tumor imaging and the mapping of sentinel lymph node, as photothermal transducers for cancer treatment, and as smart carriers for controlled release with a near-infrared laser.

Figure 1.

Schematic illustrations summarizing four major types of Au nanocages derived from different types of Ag templates: a single-crystal cube with sharp corners; a single-crystal cube with truncated corners; a single-crystal octahedron with truncated corners; and a polycrystalline, quasi-spherical particle.

Figure 2.

A) Schematic image illustrating the setup used for synthesizing Ag nanocubes on a scale of 0.1 g per batch. B) SEM image of the as-synthesized Ag nanocubes, which were 45 nm in edge length. The inset shows a transmission electron microscopy (TEM) image of the same sample. C) Schematic illustrating the setup used for synthesizing Au nanocages on a scale of 0.1 g Ag nanocubes. D) TEM image of a typical sample of Au nanocages, which were 55 nm in edge length.

Figure 3.

A) Schematic illustrating Au nanocages whose surface had been modified with various functional groups. B) Uptake of surface-modified Au nanocages by SK-BR-3 cells after incubation at 37 °C for 24 h, followed by etching with 0.34 mM I₂ for 5 min. N represents the number of Au nanocages taken up per cell. The number of samples tested for each data point was six. Reproduced with permission.^[22]

Figure 4.

A) Biodistribution of PEGylated Au nanocages in tumor-bearing mice intravenously administrated with 100 μL of the nanocages (8.4 × 10¹² particles mL⁻¹). The amount of Au in the tissue samples were analyzed by ICP-MS at three different time points. Each data point represents the mean value for n = 4 and the bar is standard deviation for the mean. B) Distribution of the PEGylated Au nanocages in the tumor. Note that E, C and EC represent edge, center, and the region between edge and center, respectively. Each data point represents the mean value for n = 3 and the bar is the standard deviation for the mean. Reproduced with permission.^[41]

Figure 5.

A) Time-course changes (%) in PA amplitude after intravenous injection of [Nle⁴,D-Phe⁷]-α-MSH- and PEG-AuNCs (n = 4 mice for each group). The PA signals increased up to 38 ± 6% for [Nle⁴,D-Phe⁷]-α-MSH-AuNCs while the maximum signal increase only reached 13 ± 2% for PEG-AuNCs at a post-injection time of 6 h (p < 0.0001). B) The average number of AuNCs accumulated in the melanomas dissected at 6 h post-injection for the two types of AuNCs as measured by ICP-MS. Here N_tumor denotes the number of AuNCs per unit tumor mass (g). The average number of [Nle⁴,D-Phe⁷]-α-MSH-AuNCs per tumor mass (3.6 ± 1.0 × 10⁸ AuNCs g⁻¹) was 3.6 times (p = 0.02) that of PEG-AuNCs (1.0 ± 1.0 × 10⁸ AuNCs g⁻¹). The inset shows the PA images of the melanoma at 6 h post-injection of [Nle⁴,D-Phe⁷]-α-MSH- and PEG-AuNCs, respectively. Reproduced with permission.^[30] Copyright 2010, American Chemical Society.

Figure 6.

A) Schematic illustrating the experimental setup of the PA imaging system. B) A typical depth-resolved B-scan PA image (x-z scan) of the suspensions of Au nanocages. C) Plots showing PA signal amplitude as a function of concentration for three types of nanostructures. Reproduced with permission.^[34] Copyright 2009, American Chemical Society.

Figure 7.

PA images acquired before (A) and after (B–D) the injection of Au nanocages: B) 5 min (SLN started to appear); C) 59 min; and D) 194 min. All images were acquired without signal averaging. PA signals from the SLN were normalized by those from adjacent blood vessels (the dotted box in Figure 7C) to minimize the ultrasonic focal effect. E) PA image (B-scan) of the SLN located 33 mm underneath the skin. F) The amplitude of PA signal as a function of imaging depth. The error bar represents standard deviation. BV, blood vessels; SLN, sentinel lymph node. Reproduced with permission.^[35] Copyright 2009 American Chemical Society.

Figure 8.

A) Plots of temperature increase for suspensions of Au nanocages with different concentrations as a function of light dose for a diode laser with a center wavelength at 808 nm. B) UV–vis–NIR spectra of the suspensions of Au nanocages before (solid line) and after (dashed line) irradiation with the diode laser at a power density of 1 W cm⁻² for 10 min. Reproduced with permission.^[41]

Figure 9.

A) Photograph of a tumor-bearing mouse undergoing photothermal treatment. 100 μL of PEGylated nanocages at a concentration of 9 × 10¹² particles per mL or saline was administrated intravenously through the tail vein as indicated by an arrow. After the nanocages had been cleared from the circulation (72 h after injection), the tumor on the right flank was irradiated by the diode laser at 0.7 W cm⁻² with a beam size indicated by the dashed circle. B–G) Thermographic images of (B–E) nanocage-injected and (F–I) saline-injected tumor-bearing mice at different time points: B,E) 1 min; C,F) 3 mi; D,G) 5 min; and E, I) 10 min. The scale bar is 5 mm. Reproduced with permission.^[41]

Figure 10.

¹⁸F-FDG PET/CT co-registered images of mice intravenously administrated with either saline or Au nanocages, followed by laser treatment: A) a saline-injected mouse prior to laser irradiation; B) a nanocage-injected mouse prior to laser irradiation; C) a saline-injected mouse after laser irradiation; and D) a nanocage-injected mouse after laser irradiation. The white arrows indicated the tumors that were exposed to the diode laser at a power density of 0.7 W cm⁻² for 10 min. E) A plot showing the ratios of laser-treated tumor (Rt tumor) to non-treated tumor (Lt tumor) ¹⁸F-FDG standardized uptake values (SUV, P < 0.001). Reproduced with permission.^[41]

Figure 11.

A) Schematic illustrating how the new release system works. Upon exposure to a NIR laser, the light is absorbed by the nanocage and converted into heat, triggering the smart polymer to collapse and thus release the pre-loaded drug. When the laser is turned off, the polymer chains will relax back to the extended conformation and terminate the release. B) A plot of the concentrations of Dox released from the Au nanocages upon heating at 45 °C for different periods of time. C) Cell viability for samples after going through different treatments: C-1) cells irradiated with a pulsed NIR laser for 2 min in the absence of Au nanocages; C-2) cells irradiated with the laser for 2 min in the presence of empty Au nanocages; and (2/5 min) cells irradiated with the laser for 2 and 5 min in the presence of Dox-loaded Au nanocages. A power density of 20 mW cm⁻² was employed for all these studies. Reproduced with permission.^[43] Copyright 2009, Nature Publishing Group.