title: A Study of Liposomal Formulations to Improve the Delivery of Aquated Cisplatin to a Multidrug Resistant Tumor.
abstract: OBJECTIVE
  This study was aimed at exploring the use of liposomes to deliver aquated cisplatin (ACP), a metabolite of CDDP, with increased potency and toxicity. Three liposomal formulations were compared for delivery of ACP to a multidrug resistant tumor.
  
  
  METHODS
  Three different liposomes (DMPC, DPPC and DSPC as the main lipid components) were loaded with ACP by the thin-film hydration method. In vitro drug release was assessed over 72 h at 37°C in PBS. The pharmacokinetics of free CDDP and the three ACP liposomes was determined using ICP-AES and their efficacy against EMT6-AR1 multidrug resistant murine breast tumor was compared.
  
  
  RESULTS
  The DSPC formulation, composed of a C18 acyl chain lipid, exhibited the slowest drug release (~2%) after 72 h at 37°C, compared to the other two formulations with decreased carbon chain lengths (C16 and C14; 7 and 25% release respectively). The pharmacokinetic profile was improved with all liposomal formulations relative to free CDDP, with clearance reduced by 500-fold for DSPC, 200-fold for DPPC and 130-fold for DMPC. The DSPC formulation displayed the highest drug accumulation in the tumor with 2-fold, 3-fold and 100-fold increases compared to DPPC, DMPC and free CDDP respectively. The DSPC formulation significantly inhibited the EMT6-AR1 tumor growth by ~90%, while the other formulations displayed no statistically significant improved activity compared to saline.
  
  
  CONCLUSIONS
  These results suggest that the DSPC liposomal formulation is a promising formulation for MDR tumor therapy over DMPC and DPPC formulations and free drug.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, 5519-2405 Wesbrook Mall, Vancouver, British Columbia, Canada, V6T 1Z3.|Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada, M5G 0A3.|Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, M5S 3M2.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, 5519-2405 Wesbrook Mall, Vancouver, British Columbia, Canada, V6T 1Z3.|Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada, M5G 0A3.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: May
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada, M5G 0A3.|Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, M5S 3M2.
authors.forename: I-Wen
authors.initials: IW
authors.lastname: Chen
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada, M5G 0A3.
authors.forename: Elijus
authors.initials: E
authors.lastname: Undzys
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, 5519-2405 Wesbrook Mall, Vancouver, British Columbia, Canada, V6T 1Z3. shyh-dar.li@ubc.ca.|Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada, M5G 0A3. shyh-dar.li@ubc.ca.|Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, M5S 3M2. shyh-dar.li@ubc.ca.
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy*; D010713:Phosphatidylcholines / Q000737:chemistry; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; D002945:Cisplatin
keywords: aquated cisplatin; cisplatin; long circulating liposome; multidrug resistant tumor