title: Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China; Pharmacy Care Center, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Yao
authors.affiliation: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zongguang
authors.initials: Z
authors.lastname: Tai
authors.affiliation: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Quangang
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Hebei North University, Hebei 075000, China.
authors.forename: Jiafei
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Chuling
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Gu
authors.affiliation: Institute of Pharmacology & Toxicology of Academy of Military Medical Sciences, Beijing 100850, China. Electronic address: gjsmmu@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: liullk@126.com.
authors.forename: Shen
authors.initials: S
authors.lastname: Gao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D035683:MicroRNAs / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C522425:MIRN34 microRNA, human; D008823:Micelles; D035683:MicroRNAs; D010455:Peptides; D012333:RNA, Messenger; D004317:Doxorubicin; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Co-delivery; Doxorubicin; Polypeptide micelle; Synergistic effect; miR-34a