Liposomal, nanoparticle, and conjugated formulations of anticancer agents.

Major advances in the use of liposomes, conjugates, nanoparticles, and microspheres as vehicles delivering pharmacologic agents and enzymes to sites of disease have occurred in the past 10 years (1–3). Pegylated-STEALTH liposomal doxorubicin (Doxil, Caelyx) was the first liposomal anticancer drug to be approved by the Food and Drug Administration, whereas paclitaxel albumin-bound particle suspension (ABI007, Abraxane) was recently approved for the treatment of metastatic breast cancer (4–6). The theoretical advantages of liposomal-encapsulated and carrier-mediated drugs are increased solubility, prolonged duration of exposure, selective delivery of entrapped drug to the site of action, improved therapeutic index, and potentially overcoming resistance associated with the regular anticancer agent (1, 2). The process by which these agents preferentially accumulate in tumor and tissues is called the enhanced permeation and retention effect (7). Although pegylated-STEALTH liposomal doxorubicin and paclitaxel albumin-bound particle suspensions are the only such agents that are approved in the United States, there are >50 other agents that are in preclinical and clinical development (Table 1). Newer generations of liposomes containing two anticancer agents with a single liposome and antibody-targeted liposomes that may improve selective toxicity are in preclinical development (8–10). In addition, antiangiogenesis agents and antisense oligonucleotides each represent rational candidates for liposomal formulations (9). The pharmacokinetic disposition of liposomal and nanoparticle agents is dependent on the carrier and not the parent drug until the drug is released from the carrier (10). Thus, the pharmacology and pharmacokinetics of these agents are complex and detailed studies must be done to evaluate the disposition of the encapsulated or conjugated form of the drug and the released active drug (11). The factors affecting the pharmacokinetic and pharmacodynamic variability of these agents remain unclear; however, it most likely include the reticuloendothelial system, which has also been called the mononuclear phagocyte system (12–14). Systemic andTissue Disposition of Liposomes