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Delivery of miR-212 by chimeric peptide-condensed supramolecular nanoparticles enhances the sensitivity of pancreatic ductal adenocarcinoma to doxorubicin

Author:
Chen, Wei, Zhou, Yue, Zhi, Xiao, Ma, Tao, Liu, Hao, Chen, Brayant Wei, Zheng, Xiaoxiao, Xie, Shangzhi, Zhao, Bin, Feng, Xinhua, Dang, Xiaowei, Liang, Tingbo
Source:
Biomaterials 2019 v.192 pp. 590-600
ISSN:
0142-9612
Subject:
adenocarcinoma, apoptosis, autophagy, blood serum, doxorubicin, drug therapy, humans, microRNA, nanoparticles, pancreatic neoplasms, patients, prognosis, ribonucleases, ubiquitin
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a destructive cancer with poor prognosis. Both novel therapeutic targets and approaches are needed to improve the overall survival of PDAC patients. MicroRNA-212 (miR-212) has been reported as a tumor suppressor in multiple cancers, but its definitive role and exact mechanism in the progression of pancreatic cancer is unclear. In this study, we developed a new chimeric peptide (PL-1) composed of plectin-1-targeted PDAC-specific and arginine-rich RNA-binding motifs which could condense miRNA to self-assemble supramolecular nanoparticles. These nanoparticles could deliver miR-212 into PDAC cells specifically and efficiently which also showed good stability in RNase and serum. Moreover, we demonstrated that PL-1/miR-212 nanoparticles could dramatically enhance the chemotherapeutic effect of doxorubicin for PDAC both in vitro and in vivo. In terms of mechanism, combined miR-212 intervention by PL-1/miR-212 nanoparticles resulted in obvious decrease of USP9X expression (ubiquitin specific peptidase 9, X-linked, USP9X) and eventually enhanced the doxorubicin induced apoptosis and autophagy of PDAC cells. These findings provide a new promising anti-cancer strategy via PL-1/miR-212 nanoparticles and identify miR-212/USP9X as a new potential target for future systemic therapy against human PDAC.
Agid:
6254064