Nanoparticle-Mediated Therapy with miR-198 Sensitizes Pancreatic Cancer to Gemcitabine Treatment through Downregulation of VCP-Mediated Autophagy

Authors

Christian Marin-Muller
Dali Li
Jian-Ming Lü
Zhengdong Liang
Osvaldo Vega-Martínez
Sue E Crawford
Mary K Estes
William E Fisher
Changyi Chen
Qizhi Yao

Publication Date

7-28-2023

Journal

Pharmaceutics

DOI

10.3390/pharmaceutics15082038

PMID

37631252

PMCID

PMC10457905

PubMedCentral® Posted Date

7-28-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

microRNA-198, pancreatic cancer, VCP, gemcitabine, drug resistance, nanoparticles, autophagy, RNAi therapeutic

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo.

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