Abstract B018: Enhanced transfection efficiency with folic acid conjugated synthetic polymer nanoparticles for high grade serous ovarian cancer

Abstract

Abstract Objective High grade serous ovarian cancer (HGSOC) represents the predominant subtype of epithelial ovarian cancer. Developing targeted therapies for HGSOC presents challenges due to its distinctive characteristic of copy number variation rather than recurrent somatic mutation. In our recent study, we proposed a novel approach for treating ovarian cancer by combining a gene editing system and nanotechnology, utilizing a cationic synthetic biopolymer, poly (γ-propargyl L-glutamine) (PPLQ). While our findings demonstrated promising results, we identified the presence of a negatively charged polymer layer, required for systematic delivery in vivo, significantly reduced both transfection efficiency and therapeutic efficacy. Therefore, an innovative approach to enhance transfection efficiency is desired to achieve improved treatment outcomes. Folate receptor alpha (FRα) is highly overexpressed in various epithelial cancers, including breast, lung, and ovarian cancer. Previous studies have revealed that FRα exhibits high tumor specificity, with epithelial ovarian cancers demonstrating 10 to 100-fold higher FRα expression levels compared to kidney, lung, and breast epithelial cells. Therefore, FRα is an attractive candidate for targeted therapy for ovarian cancer. Method In this study, we conjugated folic acid (FA), which has high affinity for FRα, to PPLQ to enhance gene delivery efficiency. Polyplexes were synthesized using FA conjugated PPLQ (FA-PPLQ) with pGL3 luciferase reporter vector. The particle size and the zeta potential were analyzed by Zetasizer, and transfection efficiency was evaluated by a luminescence assay. Result Compared to the positively charged PPLQ polyplexes, +55.5 mV, the FA-PPLQ polyplexes showed highly negative surface charges of -43.8 mV. The particle size was slightly increased from 35.07 ± 0.5422 for the PPLQ polyplexes to 48.63 ± 0.4239 for the FA-PPLQ polyplexes. The luminescence assay using a pGL3 luciferase reporter vector demonstrated a 74.4% improvement in transfection efficiency with FA conjugation compared to the negatively charged polymer layer. Conclusion Through the conjugation of folic acid to a cationic biopolymer, we successfully achieved enhanced transfection efficiency compared to a negatively charged polymer layer. Notably, the FA-PPLQ polyplexes exhibited a negative surface charge, which is advantageous for in vivo delivery. The results suggest that folic acid conjugation on the surface of polyplexes has a great promise as an effective approach for targeted gene therapy in HGSOC. Citation Format: Chaebin Lee, Kevin Elias. Enhanced transfection efficiency with folic acid conjugated synthetic polymer nanoparticles for high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B018.