Abstract P063: Novel prodrugs coupled with albumin nanoparticle encapsulation improves antitumor effects of the nucleoside analog gemcitabine

Abstract

Abstract Nucleoside analogs such as gemcitabine have been widely used to treat many solid tumors. Despite their near universal use and well understood mechanisms of action, this class of chemotherapeutic agents has notable shortcomings including rapid metabolism, limited systemic exposure, acquired resistance, and dose-limiting toxicities. Albumin-based nanoparticles offer several advantages for drug delivery including direct tumor targeting, low risk of immunogenicity, and ease of synthesis and manufacturing. We have modified numerous nucleoside drugs of clinical significance to form new prodrugs and use nanoparticle encapsulation in an attempt to improve the therapeutic index of the parent drugs. Different prodrugs of gemcitabine were designed to evade drug resistance mechanisms, and methods were developed to form stable lyophilized nanoparticle formulations. Nanoparticles were characterized by particle size (~40-65 nm) and polydispersity, and dose-dependent effects on the proliferation of human tumor cell lines were compared to the response to the parent drug gemcitabine. To evaluate effects in vivo, nanoparticle formulations were dosed intravenously (IV) to immunocompromised mice bearing patient-derived xenografts (PDx). The prodrug JTX-836 (IC50=0.46 nM) was ~10x more potent against BxPC-3 pancreatic adenocarcinoma cells than the parent gemcitabine (IC50 = 5.2 nM) in vitro. IV dosing of JTX-836 albumin nanoparticle formulation improved tumor growth inhibition in PDx models of both pancreatic ductal adenocarcinoma (CTG-0282 TumorGraft, Champions Oncology) and ovarian cancer (CTG-1180, Champions Oncology) when compared to IV gemcitabine dosing. These results demonstrate the potential for nanoparticle encapsulation of prodrugs to improve the antitumor activity of existing nucleoside analog therapeutics and support continued development of albumin-based delivery of gemcitabine for the treatment of human cancer. Citation Format: Neil Raheja, Jason Kahana, Robin Jackman, Curtis Monnig. Novel prodrugs coupled with albumin nanoparticle encapsulation improves antitumor effects of the nucleoside analog gemcitabine [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P063.