Abstract TMIM-083: A TWO-STEP TARGETING STRATEGY UTILIZING GLYCOENGINEERED MESENCHYMAL STEM CELLS FOR OVARIAN CANCER

Abstract

Abstract Current tumor targeted drug delivery systems suffer from a lack of selectivity for tumor cells. We propose a two-step tumor targeting strategy to improve the delivery of therapeutic agents to metastatic ovarian cancer. The two-step targeting approach relies on the introduction of non-natural targets (azide functional groups) in the tumor tissue, followed by the delivery of drug-loaded polymeric nanoparticles that are surface modified (with dibenzyl cyclooctyne; DBCO) and have high affinity for these synthetic targets. The objective of the present study was to determine the in vivo efficacy of two-step targeting in a clinically-realistic, patient-derived xenograft (PDX) model of ovarian cancer. The DBCO functionalized, paclitaxel (PTX)-loaded nanoparticles (16.2% w/w PTX; diameter 320 ± 10 nm; and zeta potential -11.5 ± 1.3 mV) were formulated using the FDA approved, biodegradable and biocompatible polymer, poly (DL-lactide-co-glycolide) (PLGA), by emulsion-solvent evaporation method. Glycoengineered mesenchymal stem cells (MSC-Az) were generated by culturing MSCs in N-azidoacetylmannosamine-tetraacylated supplemented media without affecting their viability or tumor homing properties. Anticancer efficacy of MSC-Az mediated two-step targeting strategy was evaluated in female athymic nude mice bearing PDX tumors. Mice with generation 2 tumors were randomly divided into four groups receiving intravenous injection of saline, PTX solution, DBCO-PTX nanoparticles, and intravenous injection of MSC-Az followed by intravenous injection of DBCO-PTX nanoparticles (MSC-Az + DBCO-PTX). We observed significantly reduced tumor growth (p <0.05) and improved survival in the group receiving MSC-Az + DBCO-PTX compared to all other groups. Furthermore, immunohistochemical analysis of the tumor tissues demonstrated that the animals treated with MSC-Az + DBCO-PTX had extensive necrosis compared to other groups, suggesting the potential of MSCs for improved tumor targeting and inhibition. In summary, our results demonstrate the potential of two-step tumor targeting strategy to enhance tumor specific delivery of conventional chemotherapeutic drugs resulting in significantly improved anti–cancer efficacy. Citation Format: Buddhadev Layek, Mihir Shetty, Tim Starr, Swayam Prabha. A TWO-STEP TARGETING STRATEGY UTILIZING GLYCOENGINEERED MESENCHYMAL STEM CELLS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-083.