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Controlled destabilization of a liposomal drug delivery system enhances mitoxantrone antitumor activity

Nature Biotechnology volume 17, pages 775–779 (1999)Cite this article

Abstract

Programmable fusogenic vesicles (PFVs) are lipid-based drug-delivery systems that exhibit time-dependent destabilization. The rate at which this destabilization occurs is determined by the exchange rate of a bilayer-stabilizing component, polyethylene glycol-phosphatidylethanolamine (PEG-PE) from the vesicle surface. This exchange rate is controlled, in turn, by the acyl chain composition of the PEG-PE. We describe in vitro and in vivo studies using PFVs as delivery vehicles for the anticancer drug mitoxantrone. We demonstrate that the PEG-PE acyl composition determined the rate at which PFVs are eliminated from plasma after intravenous administration, and the rate of mitoxantrone leakage from PFV. The nature of the PEG-PE component also determined the antitumor efficacy of mitoxantrone-loaded PFV in murine and human in murine and human xenograft tumor models. Increased circulation time and improved activity were obtained for PFV containing PEG-PE with an 18-carbon acyl chain length, as a result of slower vesicle destabilization.

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Figure 1: Mechanism of action of PFVs.
Figure 2: Influence of PEG-PE acyl composition on plasma elimination of mitoxantrone-loaded PFV after intravenous administration.
Figure 3: Accumulation of (A) PFVs and (B) mitoxantrone in the liver after intravenous administration.
Figure 4: Effect of mitoxantrone bioavailability on cell survival .
Figure 5: Therapeutic activity of mitoxantrone-loaded PFV.

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Acknowledgements

This research was supported by a grant from the National Cancer Institute of Canada (T.D.M. and M.B.B.) through funds provided by the Canadian Cancer Society. G.A-H is a recipient of GREAT Fellowship from the Science Council of British Columbia.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, The University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    Gitanjali Adlakha-Hutcheon, Clifford R. Shew, Thomas D. Madden & Thomas D. Madden

  2. Division of Medical Oncology-Advanced Therapeutics British Columbia Cancer Agency, 600 West 10th Ave., Vancouver, V5Z 4E6 , British Columbia, Canada

    Marcel B. Bally

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  1. Gitanjali Adlakha-Hutcheon
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Correspondence to Thomas D. Madden.

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Adlakha-Hutcheon, G., Bally, M., Shew, C. et al. Controlled destabilization of a liposomal drug delivery system enhances mitoxantrone antitumor activity. Nat Biotechnol 17, 775–779 (1999). https://doi.org/10.1038/11710

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