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OtherDRUG METABOLISM AND DISPOSITION

Receptor Mediated Delivery of Daunomycin Using Immunoliposomes: Pharmacokinetics and Tissue Distribution in the Rat

Jörg Huwyler, Jing Yang and William M. Pardridge
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1541-1546;
Jörg Huwyler
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Jing Yang
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William M. Pardridge
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Abstract

Pharmacokinetics and tissue distribution of daunomycin and different liposomal formulations of daunomycin were determined. Special emphasis was thereby given to immunoliposome-mediated drug delivery. Three different types of 85 nm liposomes were used for this study: 1) conventional liposomes, 2) liposomes sterically stabilized with 2000 Dalton polyethylene glycol and 3) immunoliposomes prepared by coupling a control IgG2a or monoclonal antibody to the distal end of the polyethylene glycol spacer. The antibody used was the OX26 monoclonal antibody to the rat transferrin receptor. Daunomycin and liposomes were administered by i.v. injection to the rat. Daunomycin and daunomycin in conventional liposomes were rapidly cleared from the plasma compartment. When compared to the free drug, daunomycin in conventional liposomes did accumulate to higher levels in liver and spleen and to lower levels in heart, lung and liver. In contrast, daunomycin in liposomes sterically stabilized with polyethylene glycol could not be detected in heart, lung, kidney, liver and spleen. Using nonspecific IgG2a isotype immunoliposomes, tissue concentrations of immunoliposomes were reduced by at least a factor of two. Attachment of more than 29 OX26 monoclonal antibodies per liposome did not increase tissue levels in heart, kidney or lung. Tissue levels of OX26 immunoliposomes were reduced in all organs by coinjection of unbound OX26. In vitro, endocytosis of fluorescent immunoliposomes by RG2 rat glioma cells was observed. These data indicate that receptor mediated drug delivery to different tissues can be achieved using OX26 conjugated immunoliposomes.

Footnotes

  • Send reprint requests to: Dr. William M. Pardridge, Professor of Medicine, Department of Medicine, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095-1682.

  • ↵1 J. H. is on leave from the Department of Anaesthesia and Research, University Hospital Basel, CH-4031 Basel, Switzerland and is recipient of a research grant from the Swiss National Science Foundation (Grant 32-42179.94).

  • Abbreviations:
    BBB
    blood-brain barrier
    DSPC
    distearoylphosphatidylcholine
    PE
    phosphatidylethanolamine
    DSPE
    distearoyl PE
    PEG
    polyethylene glycol
    PEG2000
    polyethylene glycol of MW 2000
    DSPE-PEG
    PEG2000covalently attached to distearoylphosphatidylethanolamine
    DSPE-PEG-Maleimide
    maleimide-polyethylene glycol-distearoylphosphatidylethanolamine
    PEG-liposomes
    PEG-conjugated liposomes
    MAb
    monoclonal antibody
    OX26
    murine MAb to the rat transferrin receptor
    OX26n immunoliposome
    a number (n) of OX26 monoclonal antibodies attached to a PEG-conjugated liposome
    %ID
    percent injected dose
    AUC
    area under the plasma concentration curve
    AUC0∞
    AUC from time-point 0 to infinity
    VD
    volume of distribution
    PS
    brain permeability-surface area
    • Received January 10, 1997.
    • Accepted May 2, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherDRUG METABOLISM AND DISPOSITION

Receptor Mediated Delivery of Daunomycin Using Immunoliposomes: Pharmacokinetics and Tissue Distribution in the Rat

Jörg Huwyler, Jing Yang and William M. Pardridge
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1541-1546;

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OtherDRUG METABOLISM AND DISPOSITION

Receptor Mediated Delivery of Daunomycin Using Immunoliposomes: Pharmacokinetics and Tissue Distribution in the Rat

Jörg Huwyler, Jing Yang and William M. Pardridge
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1541-1546;
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