Targeted Photothermal Ablation of Murine Melanomas with Melanocyte-Stimulating Hormone Analog-Conjugated Hollow Gold Nanospheres

Purpose: To develop melanoma-targeted hollow gold nanospheres (HAuNS) and evaluate their potential utility for selective photothermal ablation in melanoma. Experimental Design: A new class of photothermal coupling agents based on HAuNS was synthesized. HAuNS were stabilized with polyethylene glycol (PEG) coating and attached with alpha-melanocyte-stimulating hormone (MSH) analog, [Nle(4) D-Phe(7)] alpha-MSH (NDP-MSH), which is a potent agonist of melanocortin type-1 receptor overexpressed in melanoma. The intracellular uptake of the NDP-MSH-conjugated PEGylated HAuNS (NDP-MSH-PEG-HAuNS) and the distribution of beta-arrestin were examined in murine B16/F10 melanoma cells. The biodistribution of NDP-MSH-PEG-HAuNS was assessed at 4 hours post i.v. injection in tumor-bearing nude mice. Photothermal ablation effect of the nanoparticles was evaluated both histologically using excised tissue and functionally by [F-18]fluorodeoxyglucose positron emission tomography. Results: NDP-MSH-PEG-HAuNS consist only of a thin gold wall with hollow interior (outer diameter, 43.5 +/- 2.3 nm; shell thickness, 3-4 nm), which displays strong and tunable resonance absorption in near-IR region (peak, 808 nm). The nanoparticles were specifically taken up by melanoma cells, which initiated the recruitment of beta-arrestins, the adapters to link the activated G-protein-coupled receptors to clathrin, indicating the involvement of receptor-mediated endocytosis. This resulted in enhanced extravasation of NDP-MSH-PEG-HAuNS from tumor blood vessels and their dispersion into tumor matrix compared with nonspecific PEGylated HAuNS. Successful selective photothermal ablation of B16/F10 melanoma with targeted HAuNS was confirmed by histologic and [F-18]fluorodeoxyglucose positron emission tomography evaluation at 24 hours post near IR-region laser irradiation at a low-dose energy of 30 J/cm(2). Conclusion: NDP-MSH-PEG-HAuNS have the potentials to mediate targeted photothermal ablation of melanoma.