Abstract 6372: Nanodrug delivery system for non-genotoxic p53 activator INZ-C

Abstract

Abstract p53 is a known tumor suppressor protein whose gene is altered in 50% of all human cancers, while its function is inactivated in the many cancers harboring wild type p53, making it an attractive target for targeted cancer therapies. In this regard, our lab had previously discovered a small molecule, Inauhzin (INZ C), as a potent non-genotoxic p53 activator. In an effort to improve the bioavailability and efficacy, we have now encapsulated the INZ C small molecule in a chitosan/cyclodextrin nanoparticle delivery system. Evaluation of in vitro/in vivo activity and protien expression suggests nanoparticle encapsulation of INZ-C (n-INZ-C) improved p53 induction and inhibition of cell growth in lung and colorectal cancers, while maintaining a minimal effect for MEF and Wi38 normal cells. These results are consistent with the significantly reduced cellular uptake observed for normal cells as compared to the cancer cells. H/E staining of tissues for mice treated with n-INZ-C reveals no toxicity to other organs as well. Additionally, n-INZ-C demonstrates the ability to block migration of cells in vitro as demonstrated by both wound healing and trans-well migration assays. Our in vivo pharmacokinetic evaluation suggests nanoparticle encapsulation doubles the half-life of INZ-C from 2.5 to 5 h. These results suggest that nanoparticle encapsulation improved activity and bioavailability of INZ-C while maintaining the non-toxic nature of INZ-C in normal cells. In addition, we unveiled GRP78 as a potential new target of INZ-C and found out that knockdown of GRP78 can alleviate the inhibitory effect of INZ-C on lung and colorectal cancer proliferation. Further studies now focus on revealing the mechanism of enhanced cellular uptake for INZ-C in cancer cells as comapred to normal cells. Thus, these results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic and also identified a novel target of INZ-C. Citation Format: Nimisha Bhattarai, Jieqiong Wang, Daniel Nguyen, Xiaoxiao Yang, Linh Helmers, Jennifer Paruch, Li Li, Yiwei Zhang, Kun Meng, Alun Wang, Janarthanan Jayawickramarajah, Binghe Wang, Shelya Zeng, Hua Lu. Nanodrug delivery system for non-genotoxic p53 activator INZ-C [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6372.