Codelivery of a miR-124 Mimic and Obatoclax by Cholesterol-Penetratin Micelles Simultaneously Induces Apoptosis and Inhibits Autophagic Flux in Breast Cancer in Vitro and in Vivo.
Penetratin is a classical cell-penetrating peptide with the potential to assist in the transmembrane delivery of proteins or drugs. However, the synthesis and application of cholesterol-penetratin (Chol-P) conjugates as nonviral delivery systems for microRNAs or drugs have not previously been reported. In this study, the amphiphilic Chol-P was shown to self-assemble into micelles and efficiently deliver miR-124 and obatoclax. The codelivered miR-124-M-Oba had a homogeneous particle size and a positive zeta potential. Treatment with miR-124 mincreased cytotoxicity, and cell proliferation, was promoted by miR-124 inhibitor-loaded micelles in MCF-7 human breast cancer cells. Moreover, the inhibitory effects on cell proliferation, colony formation, and cell migration were increased in the miR-124-M-Oba group compared to the miR-124-M group. miR-124-M-Oba induced higher levels of mitochondrial apoptosis via Bax and caspase-9 activation. In addition, we found that the cationic Chol-P and miR-124-M could potently induce autophagy, and miR-124 was degraded in the corresponding autophagolysosomes. The obatoclax encapsulated in miR-124-M-Oba could inhibit the degradation of miR-124 and p62 in autophagolysosomes, which consequently maintained the concentration of miR-124 in breast cancer cells. Furthermore, miR-124-M-Oba potently inhibited tumor growth in subcutaneous xenograft breast cancer models. In summary, the miR-124-M-Oba prepared in this work showed improved apoptosis induction and autophagic flux inhibitory effects in MCF-7 cells, and miR-124-M-Oba may have potential applications in breast cancer therapy.
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Nan
N
Zhang
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Yan
Y
Huang
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Fengbo
F
Wu
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Yinbo
Y
Zhao
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Xiang
X
Li
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Pengfei
P
Shen
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Lu
L
Yang
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Yan
Y
Luo
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Li
L
Yang
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, Department of Pharmacy and Department of Urology, West China Hospital, West China Medical School, Sichuan University , Chengdu 610041, P.R. China.
Gu
G
He
D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D057846:Cell-Penetrating Peptides; D002784:Cholesterol / Q000737:chemistry*; D005260:Female; D006801:Humans; D007211:Indoles; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D014945:Wound Healing / Q000187:drug effects
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D007211:Indoles; C509207:MIRN124 microRNA, human; D008823:Micelles; D035683:MicroRNAs; D011758:Pyrroles; D002784:Cholesterol; C414409:penetratin; C520962:obatoclax
apoptosis; autophagic flux; breast cancer; miR-124; obatoclax; penetratin