title: Co-delivery of doxorubicin and P-gp inhibitor by a reduction-sensitive liposome to overcome multidrug resistance, enhance anti-tumor efficiency and reduce toxicity.
abstract: To overcome multidrug resistance (MDR) in cancer chemotherapy with high efficiency and safety, a reduction-sensitive liposome (CL-R8-LP), which was co-modified with reduction-sensitive cleavable PEG and octaarginine (R8) to increase the tumor accumulation, cellular uptake and lysosome escape, was applied to co-encapsulate doxorubicin (DOX) and a P-glycoprotein (P-gp) inhibitor of verapamil (VER) in this study. The encapsulation efficiency (EE) of DOX and VER in the binary-drug loaded CL-R8-LP (DOX + VER) was about 95 and 70% (w/w), respectively. The uptake efficiencies, the cytotoxicity, and the apoptosis and necrosis-inducing efficiency of CL-R8-LP (DOX + VER) were much higher than those of DOX and the other control liposomes in MCF-7/ADR cells or tumor spheroids. Besides, CL-R8-LP (DOX + VER) was proven to be uptaken into MCF-7/ADR cells by clathrin-mediated and macropinocytosis-mediated endocytosis, followed by efficient lysosomal escape. In vivo, CL-R8-LP (DOX + VER) effectively inhibited the growth of MCF-7/ADR tumor and reduce the toxicity of DOX and VER, which could be ascribed to increased accumulation of drugs in drug-resistant tumor cells and reduced distribution in normal tissues. In summary, the co-delivery of chemotherapeutics and P-gp inhibitors by our reduction-sensitive liposome was a promising approach to overcome MDR, improve anti-tumor effect and reduce the toxicity of chemotherapy.
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , China and.|b Department of Pharmaceutical Engineering , School of Bioengineering, Xihua University , Chengdu , China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , China and.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , China and.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , China and.
authors.forename: Yayuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , China and.
authors.forename: Qianyu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , China and.
authors.forename: Rui
authors.initials: R
authors.lastname: Ran
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , China and.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems , Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , China and.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D002966:Clathrin / Q000737:chemistry* / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D014700:Verapamil / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002966:Clathrin; D004337:Drug Carriers; D008081:Liposomes; D009842:Oligopeptides; C448619:octaarginine; D004317:Doxorubicin; D014700:Verapamil
keywords: Co-delivery; P-glycoprotein; liposomes; multidrug resistance; reduction-sensitive