(Verbatim from Abstract) The long range goal of this project is to develop the biomedical potential of expanded porphyrins. The rich nature of this potential, although far from being fully tapped, is already beginning to be realized in the case of the texaphyrins. Currently, two different water soluble lanthanide(III) texaphyrin complexes, GD-Tex and Lu-Tex, are being tested clinically. The first of these, known by the trade name XCYTRIN(TM) and the generic name motexafin gandolinium, is in a pivotal Phase III clinical trial as a potential enhancer of X-ray radiation therapy (XRT) for patients with metastatic cancers to the brain. The second, to which the generic name motexafin lutetium has been assigned, is being tested in various formulations as a photosensitizer for use in (i) the photodynamic treatment of recurrent breast cancer (LUTRIN(TM); Phase II clinical trials complete), (ii) photoangioplastic reduction of atherosclerosis involving peripheral arteries (ANTRIN(TM); Phase II testing ongoing) and (iii) light-based treatment of age-related macular degeneration (OPTRIN(TM); currently in Phase I clinical trials). The cancer-related aspects of these trials, sponsored by Pharmacyclics, Inc., a company the PI helped co-found, are being complemented by numerous NCI-supported Phase I studies that are focused on such diverse and important indications as primary brain cancer, lung cancer, breast cancer, colrectal cancer and pancreatic cancer. The present application is designed to support these clinical trials while allowing the medically targeted chemistry of expanded porphyrins to become better developed. Specifically, funds are requested to enable the mechanism of the Gd-Tex-mediated XRT effect to be elucidated at both the chemical and biochemical levels and to allow for the synthesis of new bifunctional conjugates that exploit the biolocalizing properties of texaphyrins to effect the cancer-specific delivery of known cytotoxic agents. These same funds will also be used to prepare a number of new expanded porphyrins and to study existing ones with the goal of generating cancer-selective MRI contrast agents, tissue and disease specific fluorescent probes, and catalysts that function as superoxide dismutase mimics or act to decompose efficiently peroxynitrite. These latter species could prove useful in the treatment of ischemia and reperfusion injury.
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