title: Evaluation of TPGS-modified thermo-sensitive Pluronic PF127 hydrogel as a potential carrier to reverse the resistance of P-gp-overexpressing SMMC-7721 cell lines.
abstract: In the present studies locally injectable docetaxel nanocrystals loaded d-alpha tocopheryl polyethylene glycol 1000 succinate-modified Pluronic F127 (DOC-NCs-TPGS-PF127) thermo-sensitive hydrogels were prepared to reverse drug resistance of P-glycoprotein (P-gp)-overexpressing human liver cancer SMMC-7721 tumors. Firstly, DOC nanosuspensions with mean particle size of 196nm were prepared and dispersed into series of mixed solutions containing PF127 and TPGS of different ratios to obtain DOC-NCs-TPGS-PF127 hydrogels. DOC NCs, exhibiting a uniform distribution and very good physical stability during three sol-gel cycles in the hydrogel network, did not influence the gelation temperature. Swelling-dependent release pattern was found for DOC NCs from hydrogels and release profiles could be well fitted by the Peppas equation. MTT test showed that hydrogels containing 0% or 0.1% TPGS had no cytotoxicity against L929 fibroblasts. Both DOC solution and DOC-NCs-TPGS-PF127 hydrogels exhibited obvious cytotoxicity against sensitive SMMC-7721 cells. When resistant SMMC7721 cells were treated, DOC-NCs-TPGS-PF127 hydrogels showed significantly higher cytotoxicity compared with DOC solution and hydrogels containing no TPGS (DOC-NCs-PF127), with markedly lower IC50 and resistant index (RI). After intratumoral injection in SMMC-7721/RT tumor xenograft Balb/c mice model, DOC-NCs-TPGS-PF127 hydrogels exhibited about 5-fold increase and 1.8-fold increase in the inhibition rate of tumor growth compared with intravenous and intratumoral injection of DOC solution, respectively. It could be concluded that TPGS-modified PF127 thermo-sensitive hydrogel was an excellent locally injectable carrier to reverse P-gp overexpression associated multi-drug resistance.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing 100048, China. Electronic address: leiglswj@126.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing 100048, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing 100048, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing 100048, China.
authors.forename: Daifeng
authors.initials: D
authors.lastname: Hao
authors.affiliation: Department of Food and Drug Technology, Shandong Vocational Animal Science and Veterinary College, No. 88 Shengli Dong Road, Weifang 261061, Shandong Province, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing 100048, China. Electronic address: zhoul304@163.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing 100048, China. Electronic address: liuguiy@live.cn.
authors.forename: Guiyang
authors.initials: G
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D020442:Poloxamer / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*; D013696:Temperature; D047368:Tumor Burden / Q000187:drug effects; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004337:Drug Carriers; D043823:Taxoids; D020442:Poloxamer; D014810:Vitamin E; D000077143:Docetaxel; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; C014225:tocophersolan
keywords: Docetaxel; Hydrogels; Multi-drug resistance; TPGS; Thermo-sensitive