(65e) PSMA-Targeted Glucose Oxidase Nanoparticles for Directed Cytotoxicity Toward Prostate Cancer Cells

Hormone-refractory prostate cancer is a deadly disease with few effective treatment options. Many types of cancer, including hormone-refractory prostate cancer, have shown susceptibility to glucose depletion and reactive oxygen species (ROS). The cytotoxic protein glucose oxidase (GOX) is of significant interest as an anticancer agent due to the ability of the enzyme to induce these effects of glucose depletion and ROS generation. Utilizing GOX as a cancer therapy, however, requires a safe and efficient delivery platform to limit GOX toxicity toward non-targeted cells while maximizing delivery to hormone-refractory prostate cancer cells. In this work, we aimed to enhance the cytotoxicity of GOX toward hormone-refractory prostate cancer cells by encapsulating the enzyme within nanoparticles permeable to glucose and target to prostate specific membrane antigen (PSMA). GOX was encapsulated within the cationic copolymer poly-L-lysine-grafted-polyethylene glycol (PLL-g-PEG) and functionalized with anti-PSMA monoclonal antibody. Characterization of the resulting nanoparticle complexes (anti-PSMA-PLL-g-PEG/GOX) indicated that they retained 80% of the encapsulated enzyme initial activity and were approximately 30 nm in diameter. PSMA-expressing LNCaP cells showed significant reductions in cell viability (~60%) following treatment with anti-PSMA-PLL-g-PEG/GOX, while negligible reductions in cell viability were observed for equivalent concentrations of unmodified GOX. Nanoparticle uptake and intracellular generation of ROS were observed in concurrence with the enhanced cytotoxicity of anti-PSMA-PLL-g-PEG/GOX toward LNCaP cells. These results suggest that the intracellular delivery of GOX is a useful approach to amplify enzyme cytotoxicity toward prostate cancer cells and could provide a basis for novel therapies against hormone-refractory prostate cancer.