title: Molecular mechanism study of chemosensitization of doxorubicin-resistant human myelogenous leukemia cells induced by a composite polymer micelle.
abstract: The present study was aimed to overcome the multidrug resistance (MDR) of tumor cells which accounts for the failure of clinical chemotherapy. A novel doxorubicin (DOX)-loaded composite micelle consisting of polyethylene glycol (PEG)-polycaprolactone (PCL)/Pluronic P105 has been developed and was proved to inhibit the drug resistance of human myelogenous leukemia (K562/ADR) cells. The modulation mechanism that DOX-loaded the composite micelle inhibited MDR was for the first time investigated at cell levels. Results indicated that the cytotoxicity in K562/ADR cells treated by DOX-loaded PEG-PCL/P105 composite micelle was about 4 times higher than DOX solution at 12 μg/mL of DOX. Confocal images showed that the DOX-loaded composite micelles gradually entered into cytoplasm and nucleus, and stayed in intracellular much longer than DOX solution. All the micelles (PEG-PCL micelle, P105 micelle and PEG-PCL/P105 composite micelle) did not change Pgp expression on the surface of K562/ADR cells. However, further study revealed that micelle containing of P105 (P105 or PEG-PCL/P105 composite micelle) significantly decreased ATP level, and consequently restricted the activity of Pgp by down-regulation of mitochondrial membrane potential. On the other hand, the PEG-PCL micelle had no effect on both mitochondrial membrane potential and ATP level of the K562/ADR cells, but its access to K562/ADR cells through endocytic pathway avoided the recognition of Pgp. The PEG-PCL/P105 composite micelle was designed based on the combination of P105-mediated down regulation of mitochondrial membrane potential the malignant cells and PEG-PCL-mediated internalization effect. Therefore, the novel composite micelle is a promising drug delivery system for anticancer drug to overcome MDR.
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Han
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Diao
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Jiang
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Ying
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Chen
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Liang
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Gao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008823:Micelles; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D020442:Poloxamer / Q000737:chemistry / Q000494:pharmacology*; D011091:Polyesters / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); D020442:Poloxamer; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000255:Adenosine Triphosphate; C519610:pluronic P105