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

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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.

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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

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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.

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    Authors and Affiliations

    1. Faculty of Pharmaceutical Sciences, University of British Columbia, 5519-2405 Wesbrook Mall, Vancouver, British Columbia, Canada, V6T 1Z3

      Yucheng Zhao, Jonathan P. May & Shyh-Dar Li

    2. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada, M5G 0A3

      Yucheng Zhao, Jonathan P. May, I-Wen Chen, Elijus Undzys & Shyh-Dar Li

    3. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, M5S 3M2

      Yucheng Zhao, I-Wen Chen & Shyh-Dar Li

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    1. Yucheng Zhao
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    Correspondence to Shyh-Dar Li.

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    Yucheng Zhao and Jonathan P. May contributed equally to this work.

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    Zhao, Y., May, J.P., Chen, IW. et al. A Study of Liposomal Formulations to Improve the Delivery of Aquated Cisplatin to a Multidrug Resistant Tumor. Pharm Res 32, 3261–3268 (2015). https://doi.org/10.1007/s11095-015-1702-6

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    • DOI: https://doi.org/10.1007/s11095-015-1702-6

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