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.

KEYWORD:

• Radiation; drug delivery; biodegradable polymer

Disclosure statement

The author reports no conflict of interest. The author alone is responsible for the content and writing of this paper. Work done in the author’s laboratory was supported by the Medical Research Council of Canada, the National Cancer Institute of Canada and the Cancer Research Society of Montreal.

Additional information

Notes on contributors

Shirley Lehnert

Shirley Lehnert graduated from London University in the UK with a PhD in biophysics. Shirley Lehnert worked in New York City doing research in radiobiology and biophysics first at the Sloane Kettering Institute and then at the Radiological Research Laboratory of Columbia University. When she moved to Canada she joined the faculty of McGill University to be professor in the Department of Oncology. She has published extensively in the fields of radiation biology, tumor biology and drug delivery.