Combined effect of heat shock protein inhibitor geldanamycin and free radicals on photodynamic therapy of prostate cancer

Abstract

Prostate cancer is the most common malignancy and the second leading cause of cancer-induced death among men. Recently, photodynamic therapy (PDT) has attracted great attention in prostate cancer treatment because of its high accuracy and no trauma. However, the hypoxic microenvironment of the tumor severely reduces the therapeutic efficacy of oxygen-dependent PDT in prostate cancer, which hampers the generation of reactive oxygen species (ROS). In addition, the PDT process induces the overexpression of pro-survival and anti-apoptotic proteins, thereby reducing the efficacy of PDT. This study proposed a novel multifunctional nanosystem for the targeted delivery of indocyanine green (ICG), 2,2′-azobis[2-(2-imidazolinI-2-yl) propane] dihydrochloride (AIBI), and heat shock protein 90 (Hsp90) inhibitor geldanamycin (17-AAG). Under near-infrared light irradiation, the photothermal effect of ICG induces AIBI decomposition and releases oxygen-independent free radicals, which rescues the hindered ICG-mediated ROS generation. Moreover, 17-AAG reduces heat resistance by inhibiting Hsp90, thereby achieving mild hyperthermia. Simultaneously, the inhibition of Hsp90 can inhibit the overexpression of its client proteins such as anti-apoptotic proteins (survivin) and androgen receptor (AR), thereby improving the efficacy of PDT and inducing prostate cancer cell apoptosis. Results show that the nanosystem enhances PDT by combining free radicals and 17-AAG, exhibiting a good anticancer effect on prostate cancer cells but less toxicity on normal cells.