Targeting of radio-enhancing drugs

Abstract

Objective Toxicity to normal tissue is frequently the dose-limiting factor in the chemotherapy and mixed modality treatments of cancer. If the radio-enhancing drug could be localized at the disease site and released slowly over time, then systemic drug toxicities could be decreased while simultaneously maintaining high drug concentrations in the tumor. These considerations support a role for a sustained release intra-tumoral delivery systems for the delivery of radio-enhancing drugs. Methods Two approaches aimed at achieving the end of localizing the radio-enhancing drug to the tumor are described. First, nanoparticles, which have a prolonged circulation time and facility for enhanced tumor targeting. Structural defects in the walls of the tumor vasculature allow the passage of particles too large to pass through the walls of normal blood vessels. This characteristic of tumor blood vessels, referred to as the enhanced permeability and retention (EPR) effect, allows relatively large entities (typically liposomes, nanoparticles, and macromolecular drugs) to pass from the blood vessels to tumor tissue and as a result nanoparticles accumulate in the tumor while being excluded from normal tissue. Second, biodegradable implanted polymers. In these devices, the radio-enhancing drug is physically trapped within the polymer matrix which is implanted in the tumor. The drug is released as the polymer degrades in response to its local environment. The degradation rate of the polymer device can be adjusted to control the rate of drug release. By this means, the level of radio-enhancing drug can be maintained at the tumor site for the duration of radiation treatment. Results and conclusions Results of experiments indicate that for both methods tumor control could be optimized by maintaining the radio-enhancing drug at a useful concentration in the tumor over a period of time compatible with the duration of fractionated radiation treatment. These studies have provided proof of principle support for the further development of this approach. To date, while some of the methods and devices for drug delivery described in this paper have been involved in clinical trials, none have so far been developed for routine clinical application.