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Clinical Pharmacology

Concept and Clinical Evaluation of Carrier-Mediated Anticancer Agents

Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA; UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; GLP Analytical Facility, UNC Lineberger Comprehensive Cancer Center and School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA; Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina, USA; Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina, Chapel Hill, North Carolina, USA

Key Words. Carrier-mediated anticancer agents • Nanoparticles • Nanosomes • Conjugates • Efficacy • Toxicity

Correspondence: William C. Zamboni, Pharm.D., Ph.D., Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, 3308 Kerr Hall CB 7360, 311 Pharmacy Lane, Chapel Hill, North Carolina 27599-7360, USA. Telephone: 919-843-6665; Fax: 919-962-0644; e-mail: zamboniwc{at}upmc.edu

Disclosure: The article discusses several investigational anticancer agents; all agents included are investigational except Doxil® and Abraxane®. W.C.Z. has acted as a consultant/investigator to Alza, Hana Biosci, IDM, Insertt, Labopharm, Mersana, Yakult, Neopharm, SuperGen, and Sanofi-Aventis.

Major advances in the use of carrier vehicles delivering pharmacologic agents and enzymes to sites of disease have occurred over the past 10 years. This review focuses on the concepts and clinical evaluation of carrier-mediated anticancer agents that are administered i.v. or orally. The primary types of carrier-mediated anticancer agents are nanoparticles, nanosomes, which are nanoparticle-sized liposomes, and conjugated agents. Nanosomes are further subdivided into stabilized and nonstabilized or conventional nanosomes. Nanospheres and dendrimers are subclasses of nanoparticles. Conjugated agents consist of polymer-linked and pegylated agents. The theoretical advantages of carrier-mediated drugs are greater solubility, longer duration of exposure, selective delivery of entrapped drug to the site of action, superior therapeutic index, and the potential to overcome resistance associated with the regular anticancer agent. The pharmacokinetic disposition of carrier-mediated agents depends on the physiochemical characteristics of the carrier, such as size, surface charge, membrane lipid packing, steric stabilization, dose, and route of administration. The primary sites of accumulation of carrier-mediated agents are the tumor, liver, and spleen, compared with noncarrier formulations. The drug that remains encapsulated in or linked to the carrier (e.g., the nanosome or nanoparticle) is an inactive prodrug, and thus the drug must be released from the carrier to be active. The factors affecting the pharmacokinetic and pharmacodynamic variability of these agents remain unclear, but most likely include the reticuloendothelial system, which has also been called the mononuclear phagocyte system. Future studies need to evaluate the mechanism of clearance of carrier-mediated agents and identify the factors associated with the pharmacokinetic and pharmacodynamic variability of carrier agents in patients and specifically in tumors.