(534f) Targeted Delivery of Glucose Oxidase Prolongs Survival of a Mouse Prostate Tumor Model

Excluding skin cancer, prostate cancer is the most common type of cancer, with more than 11% of men developing prostate cancer at some point in their life. In recent years, various therapeutic strategies have been introduced for the treatment of prostate cancer, including reactive oxygen species, specifically glucose oxidase (GOX). To improve efficacy and reduce its toxicity and immunogenicity, however, a targeted system is needed to deliver and retain GOX within the tumor. In this study, we encapsulated GOX using poly-l-lysine-grafted-polyethylene glycol (PLL-g-PEG) nanoparticles (NPs) and conjugated an antibody to the polymeric shell to target prostate-specific membrane antigen (PSMA), providing a tumor-specific treatment.

A library of NPs with different molecular weights of PLL and different degrees of PEGylation (2%, 10%, and 20%) was synthesized and screened for encapsulation and delivery of GOX. The NPs were characterized using NMR, DLS, zetapotential, and SDS PAGE to verify the degree of PEGylation, particle size, surface charge, and the stability of the NPs, respectively. The cytotoxicity of the GOX-NPs toward prostate cancer cells was evaluated on PSMA-expressing (LNCaP and RM1-PGLS) and non-PSMA-expressing (PC3) cell lines. The results showed that the targeted NPs were more cytotoxic toward targeted, PSMA-expressing prostate cancer cells than toward non-targeted cells. Further, the study showed that encapsulation and targeting of GOX lowered the therapeutic concentration below that normally demonstrating cellular cytotoxicity.

The efficacy of the NPs was evaluated in vivo using a mouse subcutaneous tumor model. The results showed that the intratumoral injection of targeted NPs led to a decrease in tumor volume and prolonged the survival of mice. Untreated mice survived an average of 8 days, and mice treated with GOX alone survived an average of 21 days. Mice treated with the GOX NPs survived an average of 37 days (a 76% improvement compared to free protein). Additionally, the in vivo toxicity of the targeted NPs was compared to GOX alone. The results showed that the encapsulation of GOX and conjugation of anti-PSMA antibodies not only increases the efficacy of GOX in treating prostate cancer but also decreased the toxicity of GOX toward non-cancerous cells, leading to fewer side effects. Finally, the immunogenicity of the NPs was determined using an ELISA assay to detect a panel of 20 cytokines that could be present in the serum of mice exposed to the NPs. The results of the study showed that the targeted NPs were nonimmunogenic. Taken together, the results show that encapsulation and targeted delivery of GOX can provide an efficient and safe therapeutic agent for the treatment of prostate cancer.