This proposal focuses on the design, synthesis, development and optimization of promising tetrapyrrole photodynamic therapy (PDT) photosensitizers for use in diagnosis and treatment of cancer and age-related macular degeneration, for use against atherosclerotic lesions, in virus eradication from blood, bone marrow purging, and for inhibition of transmissible spongiform encephalopathies [bovine (BSE), sheep (scrapie) and human forms (Creutzfeld-Jacob disease)]. PDT is a binary therapy involving light-activation of a photosensitizer that has been targeted to specific cells. This results in the generation of singlet oxygen and other cytotoxic species that cause disease cell destruction while sparing healthy tissues. There are only two FDA-approved tetrapyrrole photosensitizers - Photofrin and Visudyne;both of these drugs are mixtures of compounds with limited selectivity for tumor tissue. It is proposed to develop new efficient organic synthesis methods to three types of tetrapyrrole photosensitizer: amino acid, peptide, and polyethylene glycol (PEG) conjugates of (1) chlorin e6, (2) isoporphyrins, and (3) benzoporphyrins and porphycenes. For the most part, the aim is to prepare cell- and specific organelle-targeted photosensitizers for the PDT treatment of diseased cells and plaque. The tetrapyrrole photosensitizers that are synthesized will be directed to specific organelles (preferably the mitochondria) by conjugation with one or more amino acid, short peptide, or PEG of defined length. Sufficient examples within any series of synthetic sensitizers will permit the investigation of mechanisms of cellular uptake, intracellular localization and cytotoxicity. Modes of cell death for the most promising sensitizers will also be determined. This research will result in structure/activity relationships that are crucial in the design and development of better and more effective PDT photosensitizers for use in cancer, cardiovascular, blood transfusion, bone marrow purging, and spongiform encephalopathy areas of medicine. Extensive preliminary studies have been completed and show viability of all aspects of the proposed research. The new drugs will also be investigated in house for cellular uptake, intracellular localization and dark/light toxicity, and with a consultant for modes of cell death (promoting apoptosis over necrosis);rapid modifications of approach will be possible based on feedback from the biological work. It will be possible to balance biochemical and physicochemical characteristics of drugs with their PDT efficacy, and to use mechanistic knowledge to develop more effective PDT sensitizers. It is intended to understand the mechanisms of cellular targeting, uptake and subcellular localization of new tetrapyrrole sensitizers and to develop new highly effective drugs for medical use.
The proposed program is of major relevance to public health because cancer remains the second most common cause of death in the USA, and macular degeneration, atherosclerosis, viral blood and bone marrow contaminants, and spongiform encephalopathies are major world problems. Photodynamic therapy (PDT) is a treatment modality already approved by the FDA that continues to gain clinical acceptance. The full potential can be realized only when new drugs with higher cellular selectivity and specificity are discovered, their mechanisms of biological action investigated, and their efficacy evaluated relative to existing modalities.
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