title: Reversing multidrug resistance by intracellular delivery of Pluronic® P85 unimers.
abstract: Pluronics have been demonstrated as excellent multidrug resistance (MDR) reversal agent in the form of unimers rather than micelles. However, the effective intracellular delivery of Pluronic(®) unimers to MDR cancer cells still remains a big challenge. To address this issue, a mixed micellar system based mainly on the pH-sensitive copolymer of poly (L-histidine)-poly (D,L-lactide)-polyethyleneglycol-poly (D,L-lactide)-poly (L-histidine) (PHis-PLA-PEG-PLA-PHis) and Pluronic(®) F127, some of which was conjugated with folate, was constructed to intracellularly deliver the unimers of Pluronic(®) P85 to MDR cells. The folate-mediated endosomal pH-sensitive mixed micelles (pHendoSM-P85/f) were prepared by a thin-film hydration method, by which Pluronic(®) P85 unimers and doxorubicin (DOX) were incoporated into the mixed micelles. The incorporation of Pluronic(®) P85 unimers was investigated by the surface tension test. The results indicated that the Pluronic(®) P85 unimers probably first inserted into the binary mixed micelles and then formed a triple-component mixed micelles with Pluronic(®) F127 and PHis-PLA-PEG-PLA-PHis as the loading content increased. Further analyzed with flow cytometry, confocal laser scanning microscopy (CLSM) and MTT assay, the micelles with inserted Pluronic(®) P85 unimers demonstrated much more cellular uptake and higher cytotoxicity against MDR cells than the triple-component mixed micelles and plain Pluronic(®) micelles. The enhanced MDR reversal effect was attributed to the successful intracellular delivery of Pluronic(®) P85 unimers to the MDR cells, which was confirmed by the subcellular colocalization of Pluronic(®) P85 unimers with mitochondria, the decreased ATP energy and mitochondrial membrane potential (MP) in the MCF-7/ADR cells. The pHendoSM-P85/f/DOX also demonstrated more dramatic antitumor efficiency and remarkable reduction of ATP energy in the MDR cells in tumors than the control formulations. The intracellular delivery of Pluronic(®) P85 unimers to the MDR cells based on the targeted and endosomal pH triggerd release mixed micelles has been demonstrated as a promising approach to reverse MDR.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, P.O. Box 42, Shenyang, Liaoning Province 110016, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.forename: Jianfu
authors.initials: J
authors.lastname: Zeng
authors.forename: Haiyang
authors.initials: H
authors.lastname: Hu
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhao
authors.forename: Mingxi
authors.initials: M
authors.lastname: Qiao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006639:Histidine / Q000031:analogs & derivatives; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D020442:Poloxamer / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D008823:Micelles; D011091:Polyesters; C507889:polylactide-polyethylene glycol-polylactide; D020442:Poloxamer; D011092:Polyethylene Glycols; D006639:Histidine; D004317:Doxorubicin
keywords: Intracellular delivery; Multidrug resistance; Pluronic(®) P85 unimers; Triggered release; pH sensitive