title: Novel pH-sensitive nanoformulated docetaxel as a potential therapeutic strategy for the treatment of cholangiocarcinoma.
abstract: BACKGROUND
  Cholangiocarcinoma (CC) is one of the fatal malignant neoplasms with poor prognosis. The traditional chemotherapy has been resistant to CC and does not improve the quality of life. The aim of the present study is to investigate the potential of chondroitin sulphate (CS)-histamine (HS) block copolymer micelles to improve the chemotherapeutic efficacy of docetaxel (DTX).
  
  
  RESULTS
  pH-responsive property of CS-HS micelles was utilized to achieve maximum therapeutic efficacy in CC. In the present study, docetaxel-loaded CS-HS micelles (CSH-DTX) controlled the release of drug in the basic pH while rapidly released its cargo in the tumor pH (pH 5 and 6.8) possibly due to the breakdown of polymeric micelles. A nanosize of <150 nm will allow its accumulation in the tumor interstitial spaces via EPR effect. CSH-DTX effectively killed the cancer kills in a time- and concentration-dependent manner and showed pronounced therapeutic action than that of free drug at all-time points. CSH-DTX resulted in higher apoptosis of cancer cells with ~30% and ~50 of cells in early apoptosis quadrant when treated with 100 and 1000 ng/ml of equivalent drug. The micellar formulations showed remarkable effect in controlling the tumor growth and reduced the overall tumor volume to 1/5(th) to that of control and half to that of free drug treated group with no sign of drug-related adverse effects. Immunohistochemical analysis of tumor sections showed that fewer number of Ki-67 cells were present in CSH-DTX treated group comparing to that of free DTX treated group.
  
  
  CONCLUSIONS
  Our data suggests that nanoformulation of DTX could potentially improve the chemotherapy treatment in cholangiocarcinoma as well as in other malignancies.
authors.affiliation: The Second Department of Oncology, The First Affiliated Hospital of the General Hospital of the PLA, Beijing, 100048, China. dunan1054@tom.com.
authors.forename: Nan
authors.initials: N
authors.lastname: Du
authors.affiliation: The Second Department of Oncology, The First Affiliated Hospital of the General Hospital of the PLA, Beijing, 100048, China. songlp556@yeah.net.
authors.forename: Lin-Ping
authors.initials: LP
authors.lastname: Song
authors.affiliation: The Second Department of Oncology, The First Affiliated Hospital of the General Hospital of the PLA, Beijing, 100048, China. lixiaosong688@yeah.net.
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Li
authors.affiliation: Department of Medical, The First Affiliated Hospital of the General Hospital of the PLA, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China. wanglei5667@gmail.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Second Department of Oncology, The First Affiliated Hospital of the General Hospital of the PLA, Beijing, 100048, China. wanling804@163.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Wan
authors.affiliation: The Second Department of Oncology, The First Affiliated Hospital of the General Hospital of the PLA, Beijing, 100048, China. mahy5466@126.com.
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Ma
authors.affiliation: The Second Department of Oncology, The First Affiliated Hospital of the General Hospital of the PLA, Beijing, 100048, China. zhaohui83110@tom.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D002809:Chondroitin Sulfates / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000737:chemistry; D000077143:Docetaxel; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006632:Histamine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008819:Mice, Nude; D008823:Micelles; D053761:Nanocomposites / Q000008:administration & dosage / Q000737:chemistry*; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; D043823:Taxoids; D000077143:Docetaxel; D006632:Histamine; D002809:Chondroitin Sulfates