Pegylated Liposomal Doxorubicin: Scientific Rationale and Preclinical Pharmacology

ABSTRACT: Liposome-encapsulated drug delivery is a methodology that has been evolving over the past 30 years. A number of liposome-encapsulated anthracycline products are in development and two, pegylated liposomal doxorubicin (PEG-LD) (Doxil) and liposomal daunorubicin (Dauno-Xome), are approved for the treatment of AIDS-related Kaposi’s sarcoma. Preclinical studies show PEG-LD to be at least as effective as traditional or “free” doxorubicin (Adriamycin) in a variety of tumor models. Pharmacokinetic studies reveal differences between PEG-LD and doxorubicin, with PEG-LD having a higher area under the concentration-time curve (AUC), lower clearance rate, and smaller volume of distribution. In addition, PEG-LD was found to selectively accumulate in cutaneous Kaposi’s sarcoma lesions of AIDS-infected individuals when compared with adjacent normal skin. Accumulating data have led to a proposed mechanism of PEG-LD accumulation in tumors: long-term circulating liposomes pass through gaps/defects in newly formed blood vessels and enter the tumor interstitium. Liposome breakdown within tumors releases doxorubicin molecules that travel deeper into the tumor, bind to nucleic acids, and result in tumor-cell killing. The ability of PEG-LD liposomes to remain intact while in circulation, retaining most of the doxorubicin in encapsulated formulation, is believed to be responsible for the reduced toxicity seen with this agent without sacrificing efficacy. [ONCOLOGY 11(Suppl 11):11-20, 1997]

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