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Radiation Targeting of Antivascular Drugs to Tumors
Tumor Cell Biology I
Background : Antivascular drugs have shown promise in treating breast cancer but have undesirable side effects in many normal tissues, are effective at or above maximally tolerated doses, and are effective best when administered after radiotherapy. A unique opportunity for targeting antivascular drugs to irradiated breast tumors exists because a) maximum effects of several antivascular drugs are only observed when they are combined with radiotherapy and b) radiotherapy upregulates several adhesion molecules. In this novel approach drug carrying particles, having appropriate ligands to radiation induced upregulated adhesion molecules on their surfaces, would be preferentially distributed to the irradiated breast tumors thereby circumventing their undesirable side effects on normal tissue. Objective/Hypothesis : We hypothesis that particle based targeted delivery of antivascular drugs to irradiated mammary tumors can circumvent side effects/limitations of combination radiation-systemic antivascular therapy. We propose that targeted delivery of antivascular drugs to therapeutically irradiated breast tumors can deliver a significantly higher local dose of antivascular drugs to the targeted tissue and reduce their normal tissue side effects. Specific Aims : 1) to develop and characterize immunoliposomes containing antivascular drugs and determine the mechanism by which these drug carriers are incorporated into irradiated endothelium ; 2) to s tudy the efficacy of targeting combretastatin and DMXAA to irradiated murine transplanted mammary tumors. Our long term goal is to develop a combined radiation/antivascular therapy for treating breast tumors in a clinical setting. Study Design : The relationship between drug carrying particle design characteristics, as well as the mechanisms by which they are incorporated into irradiated endothelium, will be investigated and optimized in vitro. The efficacy of this radiation/targeting approach in controlling tumor volume in two different transplanted murine mammary tumor models (MCa-4 and MCa-35) will be investigated. Potential Outcomes and Benefits of the Research : Effects of ionizing radiation, which is often used to treat breast cancer, can be limited to the tumor and the immediate normal tissue surrounding it thus providing a unique opportunity for targeting antivascular drugs to breast tumors. This novel targeted delivery approach could be extended to delivery of chemotherapeutic drugs, genes, contrast agents, etc.
Breast cancer patients are often treated with radiation therapy, chemotherapy or a combination of both. In most cases, using modern clinical radiotherapeutic techniques, radiation damage can be limited to a core of diseased tissue and the immediate normal tissue surrounding it. Similarly, it would be ideal for a chemotherapeutic agent or a gene to be delivered only to the cancerous tissue and not to healthy normal tissue. Normal tissue damage caused by many anti-cancer drugs is a limiting factor in the development of more aggressive treatments for breast cancer. Normal tissue damage resulting in symptoms such as weakness and nausea significantly contributes to the quality of life reduction in many patients undergoing breast cancer treatment. This proposal seeks to develop a novel approach for selectively targeting drug carrying particles carrying molecules on their surfaces which preferentially adhere to other molecules expressed on the vasculature of irradiated breast tumors. Ideally these drug carrying particles would bind to the irradiated breast tumors and not bind to non-targeted normal tissue. The immediate goal of this proposal is to provide proof that this novel therapeutic approach is feasible and to develop the methodology to enable one to test this approach in human breast cancer patients. This study will also enhance our understanding of how radiation therapy affects the inflammatory system in breast cancer patients. The long-term goal of this project is to develop a drug delivery scheme to selectively target drug/gene carriers to breast tumors that have been irradiated for therapeutic purposes. I n collaboration with our clinical co-P.I. (Dr. Curtis Miyamoto , Chair, Department of Radiation Oncology, Temple University ) we will explore the possibility of extending our studies to clinical trials in years 2-3 of this project.