Abstract 5699: Development of Elephant <i>TP53</i> loaded lipidoid nanoparticles for the treatment of non-small cell lung cancer and colon cancer

Abstract Worldwide, lung cancer and colon cancer are the most frequently diagnosed cancers with high mortality. Targeted therapy, including small molecule inhibitors and monoclonal antibodies of various oncogenic proteins, has improved survival, but the development of resistance remains a significant issue. TP53 is a critical tumor suppressor gene and loss of function occurs in over 50% of all human cancers. In lung and colon cancer, the evolutionary conserved codons of the tumor suppressor gene TP53 are frequently mutated. Among the range of mammalian species, elephants develop less cancer than predicted based on their size and lifespan. The search for potential mechanism of cancer defense in elephants revealed that elephants possess 19 retrogene copies of TP53 in addition to ancestral TP53. Elephant cells exposed to DNA damage undergo significantly more apoptosis than human cells, and increased apoptosis is associated with increased TP53 activity. Specifically, elephant TP53 (EP53) induced mitochondrial mediated apoptosis in human cancer cells. The objective of the current research work was to 1) To investigate the anticancer activity of ancestral elephant TP53 in various non-small cell lung cancer and colon cancer cell lines and 2) develop and optimize elephant TP53 loaded lipidoid nanoparticles. Ancestral elephant TP53 (EP53) showed significant anticancer activity at doses 500 ng-125 ng in A549, H460, HT29 and HCT116 (p&amp;lt;0.05). The combination of EP53 with p53 activators and DNA damaging agents is under investigation. Amongst various transfecting reagents screened, Fugene® showed maximal transfecting efficiency for EP53 with minimal reagent toxicity. Apoptotic assay confirmed the anticancer activity of EP53. Building on the promising activity of EP53 in human lung and colon cancer cells; we further investigated formulation strategies to deliver EP53 into tumor effectively. Being a large, anionic, hydrophilic structure, a plasmid/gene poses tremendous challenges in in vivo delivery. Non-viral gene delivery by cationic ionizable lipidoid was developed for in vivo delivery of EP53. Lipidoid nanoparticles prepared using DSPC, cholesterol, DOPE, DMG-PEG-2000, DOTAP and C12-200 showed particle size of 73.98 nm with +49 mV zeta potential. High transfection (EP53 with EGFP) with complete binding of the gene (agarose gel electrophoresis) to the lipoid was observed at a 1:10 ratio of gene:lipidoid. Further, in vitro assays and tumor marker analysis are currently ongoing. Citation Format: Bhoomi Dholariya, Akanksha Patel, Joshua Schiffman, Aaron Rogers, Lisa Abegglen, Ketan Patel. Development of Elephant TP53 loaded lipidoid nanoparticles for the treatment of non-small cell lung cancer and colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5699.