Abstract A033: Intraperitoneal administration of LHRHR targeting peptides for siRNA delivery to ovarian tumor tissue

Abstract RNA-interference (RNAi) therapies offer a promising approach to slowing ovarian cancer progression and metastasis by inhibiting pro-tumorigenic gene expression using RNA molecules such as small interfering RNA (siRNA). The effective delivery of siRNA is hindered by key challenges, including enzymatic degradation, immunogenic responses, minimal cellular uptake, and rapid systemic clearance, highlighting the need for a delivery system to achieve effective gene silencing. To overcome these challenges, we previously designed a fusogenic peptide (DIV3W) and targeting peptide (GF-LD) to facilitate siRNA delivery and gene silencing in ovarian cancer. Our GF-LD peptide was specifically designed to target ovarian cancer cells, consisting of a luteinizing hormone- releasing hormone receptor (LHRHR) targeting region coupled to a fusogenic region with an enzyme-cleavable linker. Our target gene CSNK2a1, which encodes the alpha subunit of casein kinase II, was selected based on earlier established in vitro studies demonstrating its overexpression and involvement in ovarian cancer progression and invasion. An in vivo mouse model was employed to examine the therapeutic value of intraperitoneal (IP) drug delivery compared to intravenous (IV) administration for our GF-LD targeting peptide for gene delivery. Female mice were inoculated with fluorescently labeled ES-2 cells in the IP cavity to model IP metastasis in advanced-stage ovarian cancer. Following tumor establishment, mice were administered DIV3W or GF-LD peptides complexed with fluorescently labeled siRNA via IP or IV tail vein injection. siRNA biodistribution was monitored using an in vivo imaging system for 48 hours post-injection. We observed increased ovarian tumor accumulation of siRNA complexed with the peptide delivery systems after IP administration compared to IV administration, supporting the potential of IP administration as a more effective method for delivering gene therapy in ovarian cancer. These results demonstrate the impact of administration route on therapeutic accumulation in ovarian tumors, which may affect therapeutic outcomes and overall treatment success. Citation Format: Kharimat L. Alatise, Chloe Jones, Ruxi Xia, Jessica Boulos, Joey LaValla, Anna Kaminski, Angela Alexander-Bryant. Intraperitoneal administration of LHRHR targeting peptides for siRNA delivery to ovarian tumor tissue [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A033.