Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy

• Published in: Journal of controlled release 2016-06, Vol.232, p.203-214
• Main Authors: Yao, Chong, Liu, Jiyong, Wu, Xin, Tai, Zongguang, Gao, Yuan, Zhu, Quangang, Li, Jiafei, Zhang, Lijuan, Hu, Chuling, Gu, Fenfen, Gao, Jing, Gao, Shen
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Apoptosis - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Co-delivery; Doxorubicin; Doxorubicin - administration & dosage; Drug Delivery Systems; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Micelles; MicroRNAs - administration & dosage; miR-34a; Peptides - administration & dosage; Polypeptide micelle; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - therapy; RNA, Messenger - metabolism; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Synergistic effect
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.04.034

The co-delivery of chemotherapeutic drugs and microRNAs (miR) represents a promising strategy for tumor therapy due to the synergistic effect achieved. In the present study, hydrophobic doxorubicin (DOX) and negatively charged miR-34a were simultaneously delivered via a reducible self-assembling disulfide cross-linked stearyl-peptide-based micellar system (SHRss) using poly(l-arginine)-poly(l-histidine)-stearoyl as the copolymer building unit. The nanoscale SHRss micelles exhibited a low critical micelle concentration (CMC) with positive surface charge. In addition, the present micellar system facilitated the escape of miR-34a from the endosome and release of DOX into the cell nucleus, leading to the downregulation of silent information regulator 1 (SIRT1) expression and inhibition of DU145 and PC3 androgen-independent prostate cancer cell proliferation. In addition, DOX and miR-34a, delivered by SHRss micelles, passively targeted tumor tissue. Furthermore, a synergistic anti-proliferative effect was observed compared with DOX or miR-34a treatment alone in vivo. Our results demonstrate that the SHRss micelles developed in the present study represent a promising approach for combined delivery of gene agents and hydrophobic chemotherapeutic drugs in cancer therapy. The effective antitumor activity and targeting effect of co-delivery of doxorubicin and microRNA-34a mediated by reducible self-assembling cationic polypeptide-based micelles in vitro and in vivo. [Display omitted]