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

• Published in: Pharmaceutics Vol. 15; no. 8; p. 2038
• Main Authors: Marin-Muller, Christian, Li, Dali, Lü, Jian-Ming, Liang, Zhengdong, Vega-Martínez, Osvaldo, Crawford, Sue E, Estes, Mary K, Fisher, William E, Chen, Changyi, Yao, Qizhi
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 28.07.2023; MDPI
• Subjects: Antibodies; Autophagy; Cancer; Cancer therapies; Cell cycle; Chemotherapy; Cytotoxicity; Drug delivery systems; Drug dosages; Drug resistance; Drug therapy; Gemcitabine; Health aspects; Kinases; Metastasis; microRNA-198; MicroRNAs; Nanoparticles; Nucleic acids; Pancreatic cancer; Plasmids; Polymers; Proteins; Tumors; VCP; Viscosity; Texas; California; Palo Alto California; United States > US
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics15082038

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.