Abstract 821: Targeting metastatic prostate cancer using planetary ball-milled (PBM) nanoparticles

Abstract

Abstract Men are most likely to develop prostate cancer (PCa), which has a high morbidity and fatality rate. Chemotherapy, the most recommended therapeutic strategy to combat PCa, has shown adverse effects on patients and develops drug-resistant PCa resulting in overall restricted survival of the patients. Many studies have demonstrated that natural compound-mediated therapy can be an effective option for treating PCa. Among the natural compounds, Thymoquinone (TQ), a derivative of Nigella sativa, has shown anti-proliferative, antioxidant, and anti-cancer effects. However, issues remain regarding its bioavailability, safety, and effective delivery system to cancer cells in vivo. In this study, we developed TQ nanoparticles (NPs) alone or in combination with DTX-encapsulated planetary ball-milled nanoparticles (PBM-NPs), formulated with starch (natural polysaccharides) inner core and biodegradable co-polymers poly (ε-caprolactone)/poly (ethylene glycol), functionalized with a prostate-specific membrane antigen (PSMA) aptamer (A10) to target the metastatic niche in PCa metastasis pre-clinical (patient-derived xenograft (PDX) and intra-tibial metastatic (LNCaP, PC-3 cells were injected directly into the tibia of SCID mice.) models. To determine the minimum effective dose (MED), efficacy, and safety of PBM-NPs, mice were treated intravenously with dose levels of vehicle control (empty-PBM-NPs), DTX alone (5 mg/kg, weekly), TQ alone (10 mg/kg, weekly), and a combination of TQ and DTX (25-fold less than maximum tolerance dose) using PBM-NPs, respectively for five weeks. Blood serum chemistry for toxicity and immunohistochemistry were performed to characterize these metastatic models. Our results showed TQ+DTX PBM NPs suppressed p-EGFR, ERK1/2, ABCB1, and Caspase3-expression, which are regulated by the EGFR-dependent pathway. We detected OPG, RANKL, PTHrP, and ET-1 immunoreactivity in all xenografts in the bone. In conclusion, sustained-release of combination PBM NPs demonstrated more significant anti-tumor activity following their conjugation to a prostate cancer cell-specific ligand, the toxicity of the drug can be reduced, and effective concentrations of the drug can be maintained locally for prolonged periods and prevention of PCa bone metastasis. Citation Format: Santosh K. Singh, James W. Lillard, Rajesh Singh. Targeting metastatic prostate cancer using planetary ball-milled (PBM) nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 821.