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Vol. 51, Issue 4, 691-744, December 1999

Optimizing Liposomes for Delivery of Chemotherapeutic Agents to Solid Tumors

Daryl C. Drummond1, Olivier Meyer2, Keelung Hong, Dmitri B. Kirpotin and Demetrios Papahadjopoulos

California Pacific Medical Center-Research Institute, Liposome Research Laboratory, San Francisco, California (D.C.D., O.M., K.H., D.K., D.P.); Department of Radiation Oncology, University of California at San Francisco, San Francisco, California (O.M., D.K.); and Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California (D.P.)

I. Introduction
II. Pharmacokinetics and Biodistribution of Liposomes and Liposomal Drug
    A. Effect of Liposome Size on Pharmacokinetic Parameters
    B. Effect of Lipid Dose on Pharmacokinetic Parameters
    C. Effect of Liposome Charge on Pharmacokinetic Parameters
    D. Effect of Membrane Packing Constraints on Pharmacokinetic Parameters
    E. Effect of Steric Stabilization on Pharmacokinetic Parameters
    F. Comparison of Pharmacokinetic Parameters for Different Liposomal Formulations
    G. Tissue Distribution of Conventional and Sterically Stabilized Liposomes
    H. Metabolism and Elimination of Liposomal Doxorubicin
III. Accumulation of Liposomal Drugs in Tumors
    A. Mechanistic Rationale for Liposome Accumulation in Tumors: Enhanced Permeability and Retention Effect Phenomenon
        1. Effect of Microvasculature Physiology.
        2. Blood-Brain Barrier.
    B. Rate and Extent of Accumulation in Tumors
    C. Hyperthermia and Vascular Permeability Factors for Increasing Vascular Permeability
    D. Sterically Stabilized versus Rapid-Release Conventional Liposome Carriers
IV. Efficacy of Liposomal Drugs in Animal Tumor Models
    A. Comparison of Efficacy for Sterically Stabilized and Conventional Liposomes
    B. Model Dependency of Results
        1. Initial Size of Tumor.
        2. Rapidly Growing versus Slowly Growing Tumors.
        3. Route of Administration.
        4. Frequency of Injection.
        5. Environment of Tumor.
    C. Efficacy with Nonanthracyclines
    D. Multidrug Resistance
V. Clinical Efficacy of Liposomal Anthracyclines
    A. AIDS-Related Kaposi's Sarcoma
    B. Treatment of Breast and Ovarian Carcinomas
VI. Toxicology of Liposomal Chemotherapy
    A. Tolerability of Liposome Components
    B. Toxicities Associated with Free Drug
    C. Effect of Liposome Encapsulation on Toxicity Profile
        1. Cardiotoxicity.
        2. Vesicant Properties.
        3. Myelosuppression.
        4. Nausea, Vomiting, and Alopecia.
        5. Hand and Foot Syndrome (Palmar-Plantar Erythrodysesthesia Syndrome).
        6. Mucositis.
        7. Reticuloendothelial System Impairment and Opportunistic Infections.
    D. Final Comparisons of Conventional and Sterically Stabilized Liposomes
VII. Stability in Plasma and Storage
    A. Physical Stability of Liposomal Drug Formulations
        1. Drug-Loading Methods.
        2. Physical Stability of Liposome Formulations with Nonanthracyclines.
        3. Drug/Lipid Ratio.
        4. Osmolarity Effects.
        5. Stabilizing against Aggregation.
    B. Chemical Stability of Drugs and Lipid Components
VIII. Bioavailability of Encapsulated Drug
    A. Release of Doxorubicin in Tumor
    B. Active Targeting of Liposomes
    C. Hyperthermia and Thermosensitive Liposomes
    D. Problems with Highly Hydrophilic Drugs and Bioavailability
IX. Conclusions
    A. Sterically Stabilized versus Rapid-Release Conventional Liposomal Formulations
    B. Conventional and Sterically Stabilized Slow-Release Systems
    C. Visions for Future
Acknowledgments
References

1 Address for correspondence: Daryl C. Drummond, Ph.D., California Pacific Medical Center-Research Institute, Liposome Research Laboratory, Room 211, 2200 Webster St., San Francisco, CA 94115. E-mail drummond{at}cooper.cpmc.org

2 Present address: TRANSGENE S.A., 67082 Strasbourg Cedex, France.

0031-6997/99/5104-0691$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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