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

• Published in: Biomaterials Vol. 192; pp. 590 - 600
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2019
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Adenocarcinoma - ultrastructure; Amino Acid Sequence; Animals; Apoptosis - drug effects; Autophagy - drug effects; Base Sequence; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - ultrastructure; Cell Line, Tumor; Doxorubicin; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Humans; Male; Mice, Nude; MicroRNAs - administration & dosage; MicroRNAs - genetics; miR-212; Nanoparticle; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - ultrastructure; PDAC; Peptides - chemistry; Ubiquitin Thiolesterase - metabolism; USP9X; miR-212; PDAC; Nanoparticle; USP9X; Doxorubicin
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2018.11.035

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.