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Studies on the myelosuppressive activity of doxorubicin entrapped in liposomes

  • Original Articles
  • Biodistribution, Liposomal Doxorubicin, Myelosuppression
  • Published:
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Summary

The myelosuppressive activity of doxorubicin encapsulated in liposomes of differing lipid composition and size was quantified in mice by measurement of changes in spleen weight, peripheral white blood cells (WBC), and bone marrow nucleated cells. Following i. v. administration of free doxorubicin at a dose of 20 mg/kg, a 90% reduction in marrow cellularity was observed on day 3. The marrow nucleated cell count was similar to control values by day 7. Administration of an equivalent dose of doxorubicin that was encapsulated in large (diameter, ∼1.0 μm) egg phosphatidylcholine/cholesterol (EPC/Chol)(molar ratio, 55∶45) liposomes induced an 80% reduction in bone marrow cellularity that lasted for periods of >7 days. Similar results were obtained following administration of large (1.0 μm) liposomal doxorubicin systems formulated with distearoylphosphatidylcholine/cholesterol (DSPC/Chol) (molar ratio 55∶45). In contrast, liposomal doxorubicin prepared using small (diameter, ∼0.1 μm) DSPC/Chol liposomes induced only a 40% reduction (day 3) in bone marrow cellularity, which returned to control values by day 7. Other indicators of doxorubicin-mediated myelosuppressive activity (spleen weight loss and peripheral leukopenia) correlated well with changes observed in marrow cellularity. An exception to this, however, was observed in animals treated with small (0.1-μm) DSPC/Chol liposomal doxorubicin, which displayed peripheral leukopenia for periods of >14 days. This extended leukopenia was not observed following administration of small (0.1-μm) EPC/Chol liposomal doxorubicin. Marrow-associated liposomal lipid and doxorubicin were quantified to determine if the extent of doxorubicin-mediated myeloid toxicity could be correlated to changes in biodistribution of the entrapped drug. It was demonstrated that 10–20 times more doxorubicin is delivered to the bone marrow when the drug is given encapsulated in largeliposomes than when it is associated with small liposomes. These data are useful in defining characteristics of liposomal preparations that modulate the myelosupressive behaviour of entrapped antineoplastic agents.

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Abbreviations

MLV:

multilamellar vesicle

LuV:

large unilamellar vesicle

SUV:

small unilamellar vesicle

EPC:

egg phosphatidylcholine

DPPC:

dipalmitoylphosphatidylcholine

DSPC:

distearoylphosphatidylcholine

Chol:

cholesterol

RES:

reticuloendothelial system

QELS:

quasielastic light scattering

FACS:

fluorescence-activated cell sorting

WBC:

white blood cell

HBSS:

HEPES buffered saline solution

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Authors and Affiliations

  1. The Canadian Liposome Co. Ltd, 308, 267 W. Esplanade, V7M 1A5, North Vancouver, British Columbia, Canada

    Marcel B. Bally, Rajiv Nayar, D. Masin, Pieter R. Cullis & Lawrence D. Mayer

  2. Department of Biochemistry, University of British Columbia, V6T 1W5, Vancouver, British Columbia, Canada

    Marcel B. Bally, Rajiv Nayar, Pieter R. Cullis & Lawrence D. Mayer

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  1. Marcel B. Bally
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  2. Rajiv Nayar
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  3. D. Masin
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  4. Pieter R. Cullis
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  5. Lawrence D. Mayer
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Bally, M.B., Nayar, R., Masin, D. et al. Studies on the myelosuppressive activity of doxorubicin entrapped in liposomes. Cancer Chemother. Pharmacol. 27, 13–19 (1990). https://doi.org/10.1007/BF00689270

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  • DOI: https://doi.org/10.1007/BF00689270

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