title: Nanomedicine-based paclitaxel induced apoptotic signaling pathways in A562 leukemia cancer cells.
abstract: In the present study, we have synthesized an amphiphilic pH-sensitive structure of poly(ethylene glycol) methyl ether-b-(poly lactic acid-co-poly(b-amino esters)) (MPEG-b-(PLA-co-PAE)) to load paclitaxel to increase the therapeutic efficacy in leukemia. The micelles exhibit excellent drug-loading capacities for paclitaxel (PTX) and exhibited a typical pH-responsive drug release pattern. The release of PTX from the micelles was significantly accelerated by decreasing pH from 7.4 to 5.0 which just fitted the pathological process. The most important advantage of this design is that the polymeric micelles provide an effective approach for rapid transport of cargo into the cytosol, which significantly increases the antitumor efficacy of PTX against K562 cancer cells. Paclitaxel-loaded polymer micelles (PTX-M) showed significantly higher cytotoxic effect than that of free PTX. The PTX-M exhibited a superior apoptosis effect in cancer cells compared to that of free PTX at all time points. We have showed that the PTX-M activated upstream of apoptosis signaling and inhibited the anti-apoptotic factors. The PTX-M remarkably increased the upregulation of Bax, caspase-3, caspase-9, and PARP-1 expression and downregulated the Bcl-2 expression in K562 cancer cells. The results show that PTX-M induced cell apoptosis through intrinsic apoptotic signaling pathway. Importantly, PTX had a remarkably prolonged plasma circulation time after administration of PTX-M. Overall, this novel cancer specific, pH-responsive, and potentially in vivo stable unimolecular micelles may provide a very promising approach for targeted cancer therapy in the effective treatment of Leukemia.
authors.affiliation: Department of Hematology, Jining NO. 1 People's Hospital, Jining City, Shandong Province, 272011, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hematology, Jining NO. 1 People's Hospital, Jining City, Shandong Province, 272011, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Jining NO. 1 People's Hospital, Jining City, Shandong Province, 272011, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Department of Hematology, Jining NO. 1 People's Hospital, Jining City, Shandong Province, 272011, China.
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, Jining NO. 1 People's Hospital, NO. 6, Jiankang Road, Jining City, Shandong Province, 272011, China. Electronic address: changyuanzhang44@163.com.
authors.forename: Chang-Yuan
authors.initials: CY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D004337:Drug Carriers; D004339:Drug Compounding; D065546:Drug Liberation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020014:K562 Cells; D007700:Kinetics; D007773:Lactates / Q000737:chemistry; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; C000595707:BCL2 protein, human; D004337:Drug Carriers; D007773:Lactates; D008823:Micelles; D011091:Polyesters; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C492425:methoxy poly(ethylene glycol)-poly(lactide); C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D017239:Paclitaxel
keywords: Apoptosis; Drug delivery; Leukemia; Paclitaxel; Polymeric micelles