Abstract 3205: MicroRNA-peptide polyelectrolyte complex nanoparticle-hydrogel composite attenuates mesothelioma growth

Abstract Diffuse pleural mesothelioma (DPM) is a biologically unusual, aggressive asbestos-associated cancer affecting the entire pleura surface. DPM defies current standard multimodal therapies due to intrinsic chemoresistance and inability to achieve negative-margin resection of complex surface anatomy. Hence, current non-specific drug regimens ultimately fail because the biology of this tumor is poorly understood and even if surgically resected, tumor inevitably recurs from residual microscopic tumor foci. These various clinical challenges led us to develop a therapeutic platform delivering microRNA (miRNA), a novel anti-cancer agent therapeutic regimen, with the goal of eradicating residual microscopic tumor foci thereby improving the efficacy of multimodal therapy. We engineered a peptide-based biodegradable hydrogel that can be injected or sprayed directly to coat anatomic surfaces (surface-fill hydrogel; SFH), functioning as a therapeutic depot. Properties of SFH allow us to specify critical composition parameters such as biopersistence time, therapeutic payload, cell-specific targeting etc. In the first step of SFH formulation, miRNA complexed with different amphiphilic cationic peptides varying in length (19-26 amino acids) and amines (9-17), to form stable nanoparticles. Flash nanocomplexation (FNC) were used to produce highly scalable and kinetically controlled assembly of miRNA-peptide polyelectrolyte complex (PEC) nanoparticles (NPs), which utilizes a confined impinging jet (CIJ) mixer to achieve turbulent micromixing of the NPs components, yielding highly uniform and stable NPs. Next, NPs were encapsulated into another peptide hydrogel, formed via self-assembly of amphiphilic cationic peptide HLT2, thus forming a surface-fill hydrogel NPs composite. The SFH-NPs composite was not toxic to DPM cells and demonstrated efficient release of miRNA-peptide NPs from the SFH matrix in-vitro. The uptake of FAM-labeled miRNA-peptide NPs was confirmed by flowcytometry. Biodistribution analysis of NPs in mice bearing luciferase-positive DPM xenografts treated locally with Cy3-miRNA-SFH composite showed that Cy3-miRNA was concentrated in tumor cells but not in other organs. Furthermore, miR-215 exhibiting potent anti-tumor activity in DPM was used to study the therapeutic efficacy of SFH miRNA-nanoparticle composites. Subcutaneous DPM xenografts treated locally with miR-215 SFH composite shrank tumor significantly. Thus, delivery of specific miRNA-peptide PEC nanoparticles via SFH therapeutic platform in preclinical models of DPM displayed potent anti-cancer effects. Together, this new generation microRNA-peptide polyelectrolyte complex nanoparticles-SFH composite is a very promising delivery platform that could be extended for a diverse array of locoregional therapies. Citation Format: Anand Singh, Anderson Caleb, Joel P. Schneider, Chuong D. Hoang. MicroRNA-peptide polyelectrolyte complex nanoparticle-hydrogel composite attenuates mesothelioma growth abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3205.