Yucheng Zhao1,2,3, Jonathan P May1,2, I-Wen Chen2,3, Elijus Undzys2, Shyh-Dar Li4,5,6. 1. Faculty of Pharmaceutical Sciences, University of British Columbia, 5519-2405 Wesbrook Mall, Vancouver, British Columbia, Canada, V6T 1Z3. 2. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada, M5G 0A3. 3. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, M5S 3M2. 4. Faculty of Pharmaceutical Sciences, University of British Columbia, 5519-2405 Wesbrook Mall, Vancouver, British Columbia, Canada, V6T 1Z3. shyh-dar.li@ubc.ca. 5. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada, M5G 0A3. shyh-dar.li@ubc.ca. 6. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, M5S 3M2. shyh-dar.li@ubc.ca.
Abstract
PURPOSE: 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. CONCLUSION: These results suggest that the DSPC liposomal formulation is a promising formulation for MDR tumor therapy over DMPC and DPPC formulations and free drug.
PURPOSE: 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 murinebreast 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-AR1tumor growth by ~90%, while the other formulations displayed no statistically significant improved activity compared to saline. CONCLUSION: These results suggest that the DSPC liposomal formulation is a promising formulation for MDR tumor therapy over DMPC and DPPC formulations and free drug.
Entities:
Keywords:
aquated cisplatin; cisplatin; long circulating liposome; multidrug resistant tumor
Authors: S C White; P Lorigan; G P Margison; J M Margison; F Martin; N Thatcher; H Anderson; M Ranson Journal: Br J Cancer Date: 2006-09-12 Impact factor: 7.640