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

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
Biomaterials 2019 v.192 pp. 590-600
adenocarcinoma, apoptosis, autophagy, blood serum, doxorubicin, drug therapy, humans, microRNA, nanoparticles, pancreatic neoplasms, patients, prognosis, ribonucleases, ubiquitin
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.