title: L-histidine-based pH-sensitive anticancer drug carrier micelle: reconstitution and brief evaluation of its systemic toxicity.
abstract: A doxorubicin (DOX)-carrier micellar system consisting of poly(histidine)(5K)-b-poly(ethylene glycol)(2K) and poly(l-lactic acid)(3K)-b-PEG(2K)-folate has been developed targeting the early endosomal pH and it have been convincingly proved that intracellular high dose strategy using such micelles is effective in overcoming multidrug resistance (MDR) of cancer cells. Due to the low DOX concentrations in the micelle solution obtained by dialysis and the lack of long-term stability of the micelles, stable and lyophilized micelle formulations were the subject of investigation reported here by using excipients of sucrose, PEG or Pluronic. The reconstituted micelle solutions were examined by particle size, pH sensitivity, and cytotoxicity for MDR cells and the results were compared with the non-lyophilized micelles. Among tested excipients, Pluronic F127 (33 wt%) added to the polymer/drug solution prior to dialysis resulted in a reconstituted product stable for a week and presented equivalent benefits as the fresh micelle formulation. The blank micelles did not present any apparent systemic toxicity in mice up to 2400 mg/kg i.v. injection (800 mg/kg day) for 3 days). The brief toxicity of reconstituted DOX loaded micelles was examined by the maximum tolerated dose (MTD), which was approximately 7.5-fold higher than free DOX and guaranteeing further animal toxicity and efficacy study.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, 421 Wakara Way, UT 84108, USA.
authors.forename: Kyung T
authors.initials: KT
authors.lastname: Oh
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.forename: Dongin
authors.initials: D
authors.lastname: Kim
authors.forename: You Han
authors.initials: YH
authors.lastname: Bae
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D004337:Drug Carriers; D005612:Freeze Drying; D019450:Genes, MDR; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008027:Light; D008823:Micelles; D010316:Particle Size; D012542:Scattering, Radiation
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D006639:Histidine; D004317:Doxorubicin