Abstract 2985: Identifying uptake and biodistribution of liposome nanoparticles associated with secretes phospholipase A2proteins and PLA2receptors within a prostate cancer

Exploiting differences in tumor pathophysiology can enhance the delivery and antitumor activity of chemotherapeutics encapsulated in drug carriers. Long-circulating nanoparticle drug carriers, such as pegylated-sterically-stabilized liposomes (SSL), can stably entrap drug, alter drug disposition, improve antitumor activity and minimize toxicity. However, control of their drug-release kinetics has limited their clinical potential. Secretory phospholipases A2 (sPLA2) are excreted and over expressed in a variety of tumors, e.g., up to 22-fold in prostate. These enzymes degrade phospholipids preferentially and have been hypothesized as targets to control drug release from lipid-based nanoparticles, such as liposomes. While they have shown activity in preclinical models, the clinical performance of these formulations has been limited. The goal of these studies was to gain insights into how sPLA2-targeted liposome formulation (SPRL) alter drug release and uptake, specifically examining the role of sPLA2 and its membrane receptor (PLA2R1). Studies were performed using a metastatic-derived human prostate adenocarcinoma cells (PC-3) and a PLA2R1 knock-down variant (PC-3-PLA2R-KD) while varying supplementation of sPLA2 enzyme isoforms (IIA, X, V). Liposomes (SSL & SPRL) were made as described previously and included DiR, a non-exchangeable near-infrared fluorescent dye. In vitro uptake and deposition of various formulations was determined using flow cytometry and fluorescence microscopy by measuring DiR and doxorubicin (fluorescent anticancer agent) entrapped within some of the formulations. Biodistribution and circulation times were determined non-invasively on an IVIS Lumina XRMS and iThera Multispectral Optoacoustic Tomography (MSOT) systems in Athymic mouse xenograft models of prostate cancer. Liposomes formulations, SPRL and SSL were 120±1 and 118±2 nm. Circulation half-life and tumor deposition was similar for both formulations, suggesting the enhanced pharmacological activity is related to release/uptake after drug extravasation.. In-vitro studies showed that PC-3-PLA2R-KD cells had greater DiR fluorescence of both formulations than wild PC-3 after 48 hr. Moreover, SPRL had greater uptake than SSL formulation (p Citation Format: Ahmed S. Alnaim, Matthew W. Eggert, Ben Nie, Nhat D. Quanch, Shanese L. Jasper, Joshua Davis, Grafton S. Barnett, Brian S. Cummings, Peter R. Panizzi, Robert D. Arnold. Identifying uptake and biodistribution of liposome nanoparticles associated with secretes phospholipase A2 proteins and PLA2 receptors within a prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2985.