PURPOSE:
Laser activated gold nanoshell thermal ablation represents a new, minimally invasive technology that offers benign tissue sparing thermal ablation of malignant tumors. We evaluated the efficacy of this technology for eradicating prostate cancer in a subcutaneous tumor model.

MATERIALS AND METHODS:
The 110 nm gold nanoshells with a 10 nm gold shell are designed to act as intense near infrared absorbers. PC-3 cells were injected on the dorsum of nude mice in 3 groups, including 1-gold nanoshell plus near infrared laser, 2-saline alone and 3-near infrared laser alone. Animals received 7.0 ml/gm body weight (low dose) or 8.5 ml/gm body weight (high dose) nanoshells via tail vein injection. Control animals received saline. A 810 nm near infrared laser with a 200 mu laser fiber and an energy setting of 4 W/cm(2) was aimed at the tumor bed for 3 minutes. Tumors were measured at days 0, 7, 14 and 21. Tissue temperature was monitored during laser activation. Tumors were harvested at day 21 and stained with hematoxylin and eosin, and for nicotinamide adenine dinucleotide diaphorase activity.

RESULTS:
We observed 93% tumor necrosis and regression in the high dose treated group. Nicotinamide adenine dinucleotide staining corroborated this finding. The ablation zone was sharply limited to the laser spot size. There was no difference in the size or tumor histology in control groups, indicating a benign course for near infrared laser treatment alone. Temperatures up to 65.4C were attained in the treated group.

CONCLUSIONS:
Laser activated gold nanoshell ablation is an effective and selective technique for prostate cancer ablation in an ectopic murine tumor model.

Silica-gold (SiO(2)-Au) nanoshells are a new class of nanoparticles that consist of a silica dielectric core that is surrounded by a gold shell. These nanoshells are unique because their peak extinctions are very easily tunable over a wide range of wavelengths particularly in the near infrared (IR) region of the spectrum. Light in this region is transmitted through tissue with relatively little attenuation due to absorption. In addition, irradiation of SiO(2)-Au nanoshells at their peak extinction coefficient results in the conversion of light to heat energy that produces a local rise in temperature. Thus, to develop a photothermal modulated drug delivery system, we have fabricated nanoshell-composite hydrogels in which SiO(2)-Au nanoshells of varying concentrations have been embedded within temperature-sensitive hydrogels, for the purpose of initiating a temperature change with light. N-isopropylacrylamide-co-acrylamide (NIPAAm-co-AAm) hydrogels are temperature-sensitive hydrogels that were fabricated to exhibit a lower critical solution temperature (LCST) slightly above body temperature. The resulting composite hydrogels had the extinction spectrum of the SiO(2)-Au nanoshells in which the hydrogels collapsed reversibly in response to temperature (50 degrees C) and laser irradiation. The degree of collapse of the hydrogelswas controlled by the laser fluence as well as the concentration of SiO(2)-Au nanoshells. Modulated drug delivery profiles for methylene blue, insulin, and lysozyme were achieved by irradiation of the drug-loaded nanoshell-composite hydrogels, which showed that drugrelease was dependent upon the molecular weight of the therapeutic molecule.

BACKGROUND AND PURPOSE:
Nanoshells (NS) are nanoparticles consisting of a dielectric silica core covered by a thin gold shell. Nanoshells can be designed to absorb near-infrared (NIR) light strongly to generate heat and provide optically guided hyperthermic ablation. Laser-activated gold nanoshells (LAGN) may offer a minimally invasive targeted ablative treatment for prostate cancer. We studied the in-vitro effectiveness of LAGN ablation on human prostate cancer cells.

MATERIALS AND METHODS:
Two human prostate cancer (PCa) cell lines, PC-3 and C4-2, were grown to 80% confluency in T medium with 5% fetal bovine serum. In order to determine a threshold concentration of gold nanoshells (GNS) needed to achieve full cellular ablation, dose titration was performed. In subsequent experiments, GNS were added to PCa cells in phosphate-buffered saline at concentrations above the predetermined threshold. The cells were then exposed to NIR light (810 nm, 88 W/cm2) for 5 minutes and stained immediately for viability using the Calcein AM assay. For determining long-term cell survival, the crystal violet assay was employed.

RESULTS:
The GNS could be evenly distributed across the culture plates. A ratio of 5000 GNS per PCa cell was critical for achieving cell kill. Cells treated with GNS + NIR demonstrated a laser-specific zone of cell death. The crystal violet viability assay confirmed consistent cell death rather than induction of cell dormancy. Cells treated with GNS alone or with NIR light alone demonstrated no toxicity.

CONCLUSION:
Laser-activated gold nanoshells can ablate human PCa cells in vitro. This nanoparticle technology is an attractive therapeutic agent for selective tumor ablation.

Metal nanoshells are core/shell nanoparticles that can be designed to either strongly absorb or scatter within the near-infrared (NIR) wavelength region ( approximately 650-950 nm). Nanoshells were designed that possess both absorption and scattering properties in the NIR to provide optical contrast for improved diagnostic imaging and, at higher light intensity, rapid heating for photothermal therapy. Using these in a mouse model, we have demonstrated dramatic contrast enhancement for optical coherence tomography (OCT) and effective photothermal ablation of tumors.

Spherical nanoparticles with a gold outer shell and silica core can be tuned to absorb near-infrared light of a specific wavelength. These nanoparticles have the potential to enhance the treatment efficacy of laser-induced thermal therapy (LITT). In order to enhance both the potential efficacy and safety of such procedures, accurate methods of treatment planning are needed to predict the temperature distribution associated with treatment application. In this work, the standard diffusion approximation was used to model the laser fluence in phantoms containing different concentrations of nanoparticles, and the temperature distribution within the phantom was simulated in three-dimensions using the finite element technique. Magnetic resonance temperature imaging was used to visualize the spatiotemporal distribution of the temperature in the phantoms. In most cases, excellent correlation is demonstrated between the simulations and the experiment (<3.0% mean error observed). This has significant implications for the treatment planning of LITT treatments using gold-silica nanoshells.

We demonstrate a new nondestructive optical assay to estimate submicron solid particle concentrations in whole blood. We use dynamiclight scattering (DLS), commonly used to estimate nanoparticle characteristics such as size, surface charge, and degree of aggregation, to quantitatively estimate concentration and thereby estimate the actual delivered dose of intravenously injected nanoparticles and the longitudinal clearance rate. Triton X-100 is added to blood samples containing gold (Au) nanoshells to act as a quantitative scatteringstandard and blood lysing agent. The concentration of nanoshells was determined to be linearly proportional (R(2) = 0.998) to the relative light scattering attributed to nanoshells via DLS as compared with the Triton X-100 micelles in calibration samples. This relationship was found to remain valid (R(2) = 0.9) when estimating the concentration of circulating nanoshells in 15-muL blood samples taken from a murine tumor model as confirmed by neutron activation analysis. Au nanoshells are similar in size and shape to other types of nanoparticles delivered intravascularly in biomedical applications, and given the pervasiveness of DLS in nanoscale particle manufacturing, this simple technique should have wide applicability toward estimating the circulation time of other solid nanoparticles.