Poster abstracts
Poster number 49 submitted by Yudhistira Tesla
Development of RNA Nanotechnology-Based Therapeutics for Chemoresistant Hepatocellular Carcinoma Inspired by Series-Circuit Christmas Bulb Mechanisms
Tesla Yudhistira (Division of Pharmaceutics and Pharmacology, College of Pharmacy; Center for RNA Nanotechnology and Nanomedicine; James Comprehensive Cancer Center, College of Medicine. The Ohio State University, Col), Peixuan Guo (Division of Pharmaceutics and Pharmacology, College of Pharmacy; Center for RNA Nanotechnology and Nanomedicine; James Comprehensive Cancer Center, College of Medicine. The Ohio State University, Col)
Abstract:
Liver cancer, particularly hepatocellular carcinoma (HCC), poses significant treatment challenges due to chemoresistance and cancer recurrence. The liver's detoxification nature and ABC (ATP-Binding Cassette) drug transporters hinder effective intracellular drug delivery. The structure and function for drug transportation are typical of ATPase biological motors concerning the multi-homosubunit structure and the revolving transport mechanism. Based on the understanding of the dsDNA translocating mechanism and the complete inhibition trial in the multi-homosubunit-revolving ATPase exemplified by the dsDNA packing motors by Phi29, we introduce an unprecedented approach to develop a potent HCC drug, mimicking the Series-Circuits of Christmas-Bulb, for which one bulb will silence the entire bulb chain. The formula has been tested using Phi29 hexameric RNA-driven DNA packaging motor, where targeting a single subunit halts the entire cassette like a Series-Circuits-Christmas-Bulb Chain, where one failed bulb disables the entire system, thus completely shut down the replication of the virus. The concept has been proved by applying RNA nanotechnology to deliver Paclitaxel and miRNA to target the HCC homomeric multi-subunit ABC drug efflux pump P-gp for effective liver cancer inhibition as demonstrated by the trial in mice. The programmable and multivalent nature of RNA nanotechnology enables the co-delivery of multiple high-payload therapeutics to identical cancer cells by co-conjugation of the liver hepatocyte ligand GalNAc, resulting in a synergetic effect
References:
1. Weitao, T.; Grandinetti, G.; Guo, P. Exploration 2023, 3, 20210056. https://doi.org/10.1002/EXP.20210056
2. Wang, H.; Ellipilli, S.; Lee, W. J.; Li, X.; Vieweger, M. Ho, Y.S.; Guo, P. J Control Release 2021, 330, 173-184
3. Jin, K.; Liao, Y.C.; Cheng, T.C.; Li, X.; Lee, W.J.; Pi, F.; Jasinski, D.; Chen, L.C.; Phelps, M.; Ho, Y.S.; Guo, P. Mol. Pharmaceutics 2024, 21, 2, 718–728
Keywords: RNA nanotechnology, Hepatocellular Carcinoma (HCC),, Series-Circuit Mechanism