Abstract 1110: A novel peptide based microRNA nanoparticle hydrogel composite attenuates mesothelioma growth
Authors: Singh Anand , Majumder Poulami , Schneider Joel , Hoang Chuong Dinh 
Published: September 2020

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer resistant to multimodal therapies. Current therapeutic drug regimens ultimately fail due to a poor understanding of the pathogenic mechanisms. After surgical resection, MPM inevitably recurs from residual microscopic tumor foci. These clinical challenges led us to design a locoregional therapeutic platform delivering microRNA (miRNA), a novel anti-cancer agent, intrapleurally, with the goal of eradicating residual microscopic tumor foci thereby improving the efficacy of multimodal therapy. We developed a peptide-based biodegradable hydrogel that can be injected or sprayed directly to coat anatomic surfaces, functioning as a therapeutic depot. Properties of the hydrogel were fine-tuned for biopersistence time, therapeutic payload, cell-specific targeting etc. In the first step of formulation, miRNA complexed with an amphiphilic cationic peptide forms stable nanoparticles. Next, miRNA-nanoparticles were encapsulated into another peptide hydrogel, formed via self-assembly of amphiphilic cationic peptide, thus forming a nanoparticle-hydrogel composite. The hydrogel could be delivered by syringe or spray to surfaces, mold to contours, adhere and maintain integrity in-vitro as well as in-vivo. The composite material was nontoxic to MPM cells and demonstrated the efficient release of miRNA-peptide nanoparticles from the large hydrogel matrix in-vitro. Tracking of Cy3-labeled scrambled miRNA-nanoparticles by confocal microscopy showed nanoparticle uptake by cells was accomplished via a clathrin-dependent endocytosis mechanism. Furthermore, we determined that late endosome escape permitted the release of intact miRNA into the cytoplasm of MPM cells. Pathologic analysis showed macrophages degrading the hydrogel material in-vivo. Cy3-miRNA-hydrogel composite injected subcutaneously in mice showed sustained miRNA release over three weeks. In mice bearing luciferase-positive MPM xenografts (pleural or peritoneal) treated locally with Cy3-miRNA-hydrogel composite, the Cy3-miRNA was concentrated in tumor cells but not in other organs. miRNAs targeting specific molecular vulnerabilities of MPM were used to study the therapeutic efficacy of miRNA-nanoparticle-hydrogel composites. Subcutaneous xenografts treated locally with MPM-specific miRNA-hydrogel composite shrank significantly. Similarly, pleural and peritoneal orthotopic xenografts treated with specific miRNA-hydrogel composite regressed over time. Kaplan-Meier analysis showed that miRNA-hydrogel treatment improved overall survival of tumor-bearing mice. Thus, delivery of specific miRNA via a locoregional therapeutic platform in preclinical models of MPM resulted in beneficial anti-cancer effects. This peptide-based material is promising for translational studies of nucleic acid-based locoregional therapy against MPM.
Citation Format: Anand Singh, Poulami Majumder, Joel Schneider, Chuong Dinh Hoang. A novel peptide based microRNA nanoparticle hydrogel composite attenuates mesothelioma growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1110.