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OtherCHEMOTHERAPY/GENE THERAPY

The Role of Tumor-Associated Macrophages in the Delivery of Liposomal Doxorubicin to Solid Murine Fibrosarcoma Tumors

Lawrence D. Mayer, Graeme Dougherty, Troy O. Harasym and Marcel B. Bally
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1406-1414;
Lawrence D. Mayer
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Graeme Dougherty
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Troy O. Harasym
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Marcel B. Bally
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Abstract

Murine fibrosarcoma tumors arising from subcutaneous inoculation of FSa-N cells exhibit 4-fold higher tumor-associated macrophage (TAM) levels than those from the FSa-R line. These solid tumors were used to assess the role of TAMs in the accumulation of liposomal anticancer drugs. Two liposomal formulations of doxorubicin were investigated: a conventional formulation composed of distearoylphosphatidylcholine (DSPC) and cholesterol and a sterically stabilized liposomal formulation composed of DSPC/cholesterol/poly (ethylene glycol)-modified distearoylphosphatidyethanolamine (PEG-PE). Circulating concentrations of PEG-PE containing liposomes 24 h after i.v. administration were 3-fold greater than those observed after administration of conventional liposomes. No differences were observed in drug retention or tumor (FSa-R or FSa-N) drug and liposomal lipid delivery when comparisons were made between different liposomal formulations. However, tumor doxorubicin concentrations were increased as much as 4-fold for liposomal formulations relative to free drug. Further, there was a 1.5- to 2-fold increase in doxorubicin delivery to TAM-enriched FSa-N tumors compared with FSa-R tumors. Fluorescence microscopy studies revealed a poor correlation between CD11b (Mac-1) positive cells (TAMs) and the appearance of doxorubicin fluorescence. These results suggest that uptake of liposomal drugs by TAMs does not account for the enhanced accumulation of liposomal drugs in solid tumors. Rather, the increased tumor drug delivery may be related to alternative TAM-mediated processes that increase tumor vascular permeability. Therapeutic studies demonstrated that increased tumor drug uptake observed for the liposomal doxorubicin formulations led to marginal improvements in antitumor activity, and it is suggested that much of the drug delivered in liposomal form is not biologically available.

Footnotes

  • Send reprint requests to: L.D. Mayer, Division of Medical Oncology, BC Cancer Agency, 600 W. 10th Ave., Vancouver, BC V5Z 4E6.

  • ↵1 This work was supported through a research grant from the Cancer Research Society, Inc. (L.D.M.) and the Medical Research Council (M.B.B.) of Canada.

  • Abbreviations:
    PC
    phosphatidylcholine
    DSPC
    distearoylphosphatidylcholine
    PEG-PE
    polyethyleneglycol-distearoylphosphatidylethanolamine
    DOX
    doxorubicin
    TAM
    tumor-associated macrophage
    RES
    reticuloendothelial system
    QELS
    quasielastic light scattering
    CHDE
    cholesterylhexadecyl ether
    EDTA
    ethylenediamine tetraacetic acid
    Chol
    cholesterol
    i.v.
    intravenous
    PBS
    phosphate-buffered saline
    FITC
    fluorescein isothiocyanate
    • Received February 12, 1996.
    • Accepted November 13, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherCHEMOTHERAPY/GENE THERAPY

The Role of Tumor-Associated Macrophages in the Delivery of Liposomal Doxorubicin to Solid Murine Fibrosarcoma Tumors

Lawrence D. Mayer, Graeme Dougherty, Troy O. Harasym and Marcel B. Bally
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1406-1414;

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OtherCHEMOTHERAPY/GENE THERAPY

The Role of Tumor-Associated Macrophages in the Delivery of Liposomal Doxorubicin to Solid Murine Fibrosarcoma Tumors

Lawrence D. Mayer, Graeme Dougherty, Troy O. Harasym and Marcel B. Bally
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1406-1414;
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