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Pharmaceutical Research

, Volume 32, Issue 10, pp 3261–3268 | Cite as

A Study of Liposomal Formulations to Improve the Delivery of Aquated Cisplatin to a Multidrug Resistant Tumor

  • Yucheng Zhao
  • Jonathan P. May
  • I-Wen Chen
  • Elijus Undzys
  • Shyh-Dar Li
Research Paper

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.

KEY WORDS

aquated cisplatin cisplatin long circulating liposome multidrug resistant tumor 

ABBREVIATIONS

ACP

Aquated cisplatin

AUC

Area under the concentration curve

CDDP

Cisplatin

CHOL

Cholesterol

Cl

Clearance

CTR1

Copper transporter 1

DLS

Dynamic light scattering

DMEM

Dulbecco’s Modified Eagle’s medium

DMPC

1, 2-dimyristoyl-sn-glycero-3-phosphatidylcholine

DPPC

1, 2-dipalmitoyl-sn-glycero-3-phosphatidylcholine

DSPC

1,2-distearoyl-sn-glycero-3-phosphatidylcholine

DSPE-PEG

1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]

EPR-effect

Enhanced permeability and retention effect

FBS

Fetal bovine serum

ICP-AES

Inductively Coupled Plasma Atomic Emission Spectroscopy

ID/g

Injected dose per gram of tissue

LCL

Long circulating liposomes

MDR

Multi-drug resistance

MLV

Multi-lamellar vesicles

MWCO

Molecular weight cut-off

NPs

Nanoparticles

PBS

Phosphate buffered saline

PDI

Polydispersity index

Pt

Platinum

RES

Reticuloendothelial system

t1/2

Half life

Vss

Steady state volume of distribution

Notes

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.

Supplementary material

11095_2015_1702_MOESM1_ESM.docx (110 kb)
ESM 1 (DOCX 109 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yucheng Zhao
    • 1
    • 2
    • 3
  • Jonathan P. May
    • 1
    • 2
  • I-Wen Chen
    • 2
    • 3
  • Elijus Undzys
    • 2
  • Shyh-Dar Li
    • 1
    • 2
    • 3
  1. 1.Faculty of Pharmaceutical SciencesUniversity of British ColumbiaVancouverCanada
  2. 2.Drug Discovery ProgramOntario Institute for Cancer ResearchTorontoCanada
  3. 3.Leslie Dan Faculty of PharmacyUniversity of TorontoTorontoCanada

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