title: D-α-tocopherol polyethylene glycol succinate-based redox-sensitive paclitaxel prodrug for overcoming multidrug resistance in cancer cells.
abstract: To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ∼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.
authors.affiliation: Tongji School of Pharmacy, ‡National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology Wuhan 430030, P.R. China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Bao
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Guo
authors.forename: Xiangting
authors.initials: X
authors.lastname: Zhuang
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Bolin
authors.initials: B
authors.lastname: Cheng
authors.forename: Songwei
authors.initials: S
authors.lastname: Tan
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D051379:Mice; D008823:Micelles; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011355:Prodrugs; D014810:Vitamin E; D011092:Polyethylene Glycols; C014225:tocophersolan; D017239:Paclitaxel