Photodynamic therapy (PDT) is a promising new cancer treatment regimen that consists of systemic administration of a photosensitizer followed by exposure of the neoplastic lesion to visible light. The most well studied photosensitizers are hema- toporphyrin derivative. (HPD) which consists of a mixture of hematoporphyrins, and a partially purified preparation of HPD, (Photofrin II), which represents an enrichment of the more hydrophobic porphyrin components in HPD. Advantages of Photofrin II are its ability to localize in neoplastic tissue and its relative lack of toxicity; disadvantages are its compositional uncertainty and lack of stability. Chemically defined photosensitizers would provide the obvious advantage of reproducibility, but importantly, offer the opportunity to synthetically modify and thereby enhance photosensitizing potency. We propose to undertake a systematic examination of a Family of o-substituted tetraphenylporphine derivatives, generally termed """"""""picket fence porphyrins,"""""""" which were designed to be comparable with organized assemblies and thus reside selectively at hydrophilic-hydrophobic interfaces. Based on our recent demonstration that meso-tetra-(o-acetylamidophenyl) porphyrin displays photosensitizing activity, we now wish to study 1) effects of varying the alkyl side chain length; 2) determine efficacy relative to the atropisomeric structure; 3) synthesize and study amino acid derivatives with varying charge type and hydrophobicity; and 4) synthesize chlorin and bacterio chlorin derivatives of the most effective picket fence porphyrins. Photosensitizing activity will be assessed by standardized and published procedures employed by us for study of HPD and Photofrin II, consisting of measurement of activity in vitro, with isolated cells and subcellular organelles, an in vivo - in vitro, paradigm that involves systemic administration to tumor-bearing rats and radiation of tumor preparations in vitro, and an in vivo protocol that is analogous to clinical PDT. We expect that results from these structure-activity relationship studies will identify those chemical properties that with facilitate design of improved phototherapeutic agents for use in PDT.
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