title: Evaluation of doxorubicin-loaded pH-sensitive polymeric micelle release from tumor blood vessels and anticancer efficacy using a dorsal skin-fold window chamber model.
abstract: OBJECTIVE
  To evaluation the doxorubicin (DOX)-loaded pH-sensitive polymeric micelle release from tumor blood vessels into tumor interstitium using an animal vessel visibility model, the so-called dorsal skin-fold window chamber model.
  
  
  METHODS
  DOX-loaded pH-sensitive polyHis-b-PEG micelles and DOX-loaded pH-insensitive PLLA-b-PEG micelles were prepared. The uptake of the micelles by MDA-MB-231 breast cancer cells in vitro and in vivo was examined using flow cytometry. The pharmacokinetic parameters of the micelles were determined in SD rats after intravenous injection of a DOX dose (6 mg/kg). The release of the micelles from tumor vasculature and the antitumor efficacy were evaluated in MDA-MB-231 breast cancer xenografted in nude mice using a dorsal skin-fold window chamber.
  
  
  RESULTS
  The effective elimination half-life t1/2 of the pH-sensitive, pH-insensitive polymeric micelles and DOX-PBS in rats were 11.3 h, 9.4 h, and 2.1 h, respectively. Intravital microscopy in MDA-MB-231 breast cancer xenografted in nude mice showed that the pH-sensitive polymeric micelles rapidly extravasated from the tumor blood vessels, and DOX carried by the pH-sensitive micelles was preferentially released at the tumor site as compared to the pH-insensitive polymeric micelles. Furthermore, the pH-sensitive polymeric micelles exhibited significant greater efficacy in inhibition of tumor growth in the nude mice.
  
  
  CONCLUSIONS
  When DOX is loaded into pH-sensitive polymeric micelles, the acidity in tumor interstitium causes the destabilization of the micelles and triggers drug release, resulting in high local concentrations within the tumor, thus more effectively inhibiting the tumor growth in vivo.
authors.affiliation: 1] State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences, Beijing 100050, China [2] YanBian University Hospital, Yanji 133000, China.
authors.forename: Zhe-Hu
authors.initials: ZH
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Ming-Ji
authors.initials: MJ
authors.lastname: Jin
authors.affiliation: YanBian University Hospital, Yanji 133000, China.
authors.forename: Chang-Gao
authors.initials: CG
authors.lastname: Jiang
authors.affiliation: YanBian University Hospital, Yanji 133000, China.
authors.forename: Xue-Zhe
authors.initials: XZ
authors.lastname: Yin
authors.affiliation: YanBian University Hospital, Yanji 133000, China.
authors.forename: Shuai-Xing
authors.initials: SX
authors.lastname: Jin
authors.affiliation: YanBian University Hospital, Yanji 133000, China.
authors.forename: Xiu-Quan
authors.initials: XQ
authors.lastname: Quan
authors.affiliation: 1] State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Chinese Academy of Medical Sciences, Beijing 100050, China [2] YanBian University Hospital, Yanji 133000, China.
authors.forename: Zhong-Gao
authors.initials: ZG
authors.lastname: Gao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001940:Breast / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D011108:Polymers / Q000737:chemistry; D019736:Prostheses and Implants; D017207:Rats, Sprague-Dawley
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin