Concept and Clinical Evaluation of Carrier-Mediated Anticancer Agents

Abstract

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. The Oncologist 2008;13: 248 -260

Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions

“…Lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox Ò ; Celsion Corporation), which consists of doxorubicin contained within a heat-sensitive liposome, was designed for adjuvant use with RFA. After LTLD administration by intravenous (IV) infusion, the liposomes selectively localize within and around tumor tissues (13) because of their heightened permeability and retention properties (14). At normal body temperatures, doxorubicin remains encapsulated within the liposomes.…”

Liposomes as nanomedical devices

“…When used in clinical settings, liposomal treatments proved to improve patient outcome dramatically, reducing some of the side effects associated with chemotherapy, such as cardiotoxicity, nausea, and vomiting, when compared to unencapsulated drugs. 63,64 Therapeutic activity of vincristine, widely used in the treatment of a number of human carcinomas, significantly increased after its encapsulation in appropriately designed liposomal systems. In fact, vincristine sulfate-liposome injection improved the therapeutic index by facilitating increased dose intensification, while maintaining a predictable and manageable safety profile.…”

A step towards a new targeted nanotherapy for pancreatic cancer

“…However, these agents suffer from several major drawbacks to their use including improper distribution upon intravenous administration, off-target effects on non-cancerous tissue, and rapid drug metabolism prior to arrival at the tumor site. 1 Alternate methods of drug delivery are actively being developed, including gene therapy and nanomedicine approaches. [1][2][3] Conventional gene therapy using viral particles to deliver DNA provides the promise of slowing disease progression.…”

“…1 Alternate methods of drug delivery are actively being developed, including gene therapy and nanomedicine approaches. [1][2][3] Conventional gene therapy using viral particles to deliver DNA provides the promise of slowing disease progression. However, this approach, too, suffers from major pitfalls including immune system activation that may result in serious consequences, including death.…”

“…12 Additionally, these plasmids will target mesothelin-overexpressing pancreatic cancer cells wherever they hide, which means that circulating mesothelin-overexpressing cancer cells destined to metastasize could also be destroyed prior to further spread of the disease. 1 Final proof of its effectiveness, of course, will be in vivo animal studies and clinical trials. The potential to provide a novel, effective new therapy for treatment of pancreatic cancer, however, is exciting.…”