title: Overcoming tumor resistance to cisplatin through micelle-mediated combination chemotherapy.
abstract: The main obstacles to cancer therapy are the inability to target cancer cells and the acquired drug resistance after a period of chemotherapy. Reduced drug uptake and DNA repair are the two main mechanisms involved in cisplatin resistance. In the present investigation, canthaplatin, a Pt(iv) pro-drug of cisplatin and a protein phosphatase 2A (PP2A) inhibitor (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester), was designed and delivered using PEG-b-PLGA micelles for combination chemotherapy. Polymer/canthaplatin micelles facilitated the delivery of the drug into cancer cells through endocytosis and diminished DNA repair by PP2A inhibition, resulting in enhanced anti-tumor efficiency and excellent reversal ability of tumor resistance to cisplatin both in vitro and in vivo. Additionally, the polymer/canthaplatin micelles could prolong drug residence in the blood and decrease the side effects when compared to cisplatin.
authors.affiliation: State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China. ybhuang@ciac.ac.cn.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Zhou
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Cong
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Qi
authors.forename: Shasha
authors.initials: S
authors.lastname: He
authors.forename: Hejian
authors.initials: H
authors.lastname: Xiong
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xie
authors.forename: Xuesi
authors.initials: X
authors.lastname: Chen
authors.forename: Xiabin
authors.initials: X
authors.lastname: Jing
authors.forename: Yubin
authors.initials: Y
authors.lastname: Huang
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D008823:Micelles; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: C000613049:(4-(3-carboxy-7-oxa-bicyclo(2.2.1)heptane-2-carbonyl)piperazine-1-carboxylic acid tert-butyl este; D001643:Bridged Bicyclo Compounds; D008823:Micelles; D009944:Organoplatinum Compounds; D010879:Piperazines; D011355:Prodrugs; D054648:Protein Phosphatase 2; D002945:Cisplatin