A Study of Liposomal Formulations to Improve the Delivery of Aquated Cisplatin to a Multidrug Resistant Tumor
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.
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.
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.
These results suggest that the DSPC liposomal formulation is a promising formulation for MDR tumor therapy over DMPC and DPPC formulations and free drug.
KEY WORDSaquated cisplatin cisplatin long circulating liposome multidrug resistant tumor
Area under the concentration curve
Copper transporter 1
Dynamic light scattering
Dulbecco’s Modified Eagle’s medium
Enhanced permeability and retention effect
Fetal bovine serum
Inductively Coupled Plasma Atomic Emission Spectroscopy
Injected dose per gram of tissue
Long circulating liposomes
Molecular weight cut-off
Phosphate buffered saline
Steady state volume of distribution
ACKNOWLEDGMENTS AND DISCLOSURES
We would like to acknowledge the Canadian Institutes for Health Research (CIHR) for assistance with funding for this project, through a combination of CIHR proof-of-principle and CIHR operating grants. SDL also received a CIHR New Investigator Award and a Young Investigator Award from the Prostate Cancer Foundation. The Ontario Institute for Cancer Research (Funded by the Government of Ontario), University Health Network and the Analest facility at the University of Toronto are also acknowledged for providing the facilities and equipment necessary to conduct this research.