Abstract B025: Star Copolymer-Mediated Delivery of Anti-miRNA Therapeutics for Pancreatic Cancer

Abstract Introduction: Pancreatic cancer has the lowest survival rate among all major cancer types, with a five-year survival rate of only 10%. Current therapies elicit only a limited response highlighting the urgent need for novel treatment strategies. RNA-based therapeutics have emerged as a promising approach for cancer treatment; however, their clinical translation is hindered by the lack of safe and effective delivery systems. Polymeric carriers are particularly attractive for RNA delivery due to their versatility, multifunctionality, and cost-effectiveness. Poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) is a cationic monomer that facilitates RNA complexation, endosomal escape, and cellular internalization. In addition, incorporating oligo(ethylene glycol) methyl ether methacrylate (OEGMA) has been shown to reduce toxicity and improve circulation time thereby enhancing in vivo performance. Materials and Methods: DMAEMA-OEGMA star copolymers with varying architectures were synthesized using group transfer polymerization. Their physicochemical properties, including hydrodynamic size, zeta potential, composition, dispersity, molar mass, pKa, and cloud point, were characterized. Polyplexes (RNA–polymer complexes) were developed by optimizing nitrogen-to-phosphate (N/P) ratios. Polyplex stability in the presence serum components was evaluated via agarose gel electrophoresis. Biocompatibility was evaluated in both 2D cell lines and 3D pancreatic cancer spheroids. Potential immunogenicity was assessed by measuring pro-inflammatory cytokine expression in macrophages using RT-qPCR. Transfection efficiency and was quantified using flow cytometry and benchmarked against gold standard transfection reagents. Endosomal escape and intracellular distribution were assessed by confocal microscopy. For translational relevance, performance was validated in 3D pancreatic cancer models engineered from fibronectin-functionalized polyurethane scaffolds, which can be tuned to mimic the biomechanical and biochemical characteristics of the tumor microenvironment. Results and Discussion: The star copolymers had molar masses around 100 kDa and hydrodynamic diameters ranging from 18–22 nm. Zeta potentials ranged from 17-20 mV and complete RNA complexation was achieved at N/P ratios of 5 or below. In 3D pancreatic cancer spheroids, the star polymers demonstrated excellent biocompatibility, with lower toxicity than polyethyleneimine (PEI), a polymer delivery standard. Several star copolymers exhibited superior transfection efficiency reaching up to 85%, compared to PEI (50%), Confocal imaging confirmed efficient cellular uptake and endosomal escape. The polymers also performed well in the scaffold-based 3D models, highlighting their translational potential. Conclusion: DMAEMA-OEGMA star copolymers exhibit a favorable balance of safety and transfection efficiency, outperforming conventional standards in both 2D and 3D models. These findings support their potential as a robust platform for the delivery of RNA therapeutics in pancreatic cancer and potentially other malignancies. Citation Format: Sofia Miron-Barroso, Eleni Chatzilakou, Shriya Varghese, Shaobai Wang, Paula Cunnea, Eirini Velliou, Alexandra E. Porter, Theoni K. Georgiou, Jonathan Krell. Star Copolymer-Mediated Delivery of Anti-miRNA Therapeutics for Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B025.