Photodynamic therapy (PDT), a promising cancer treatment regimen, consists of systemic administration of a photosensitizer followed by exposure of the neoplasm to visible light of appropriate spectral characteristics. The most studied photosensitizer, Photofrin II, has demonstrated clinical efficacy and relatively little systemic toxicity. However, Photofrin II is a mixture of oligomers, having ether and ester linkages. Due to its compositional uncertainty and chemical instability, we began an investigation of selected o-substituted tetraphenylporphyrin derivatives, termed """"""""picket fence porphyrins"""""""" (PFPs), and determined the influence of alkyl side chain length and atropisomer configuration on their photosensitizing activity in vitro. During the initial period of this project, we demonstrated that 3,1 TPro was an effective photosensitizer for PDT in vivo, prolonging the doubling of tumor size by 8 times that seen in controls. These positive findings form the basis of logical and mandatory next step experiments to optimize the efficacy of PFPs for use in PDT. We are now proposing to synthesize radioactive ring-labeled 3,1 isomers of PFPs and to use these compounds to 1) ascertain the pharmacokinetic properties of 3,1 TPro, TAc and THex in tumor-bearing rodents in order to evaluate the effects of alkyl side chain length on uptake and retention in normal tissues and tumors; 2) determine the relationship between administered dose level and tissue and tumor levels, as well as any relationship to tumor size; 3) establish the relationship between the quantity of PFP in the vascular compartment, normal tissues and in tumors, and anti-tumor efficacy in vivo; 4) explore mechanisms of actions and subcellular distribution of PFPs, and their photosensitizing activities will be measured and related to alkyl side chain length, as well as relating differences in extracellular and intracellular PFP levels with PDT-induced alterations in phosphate metabolites by use of 31P NMR spectroscopy of tumors in situ and by NMR imaging; and 5) assess photosensitizing activities of novel phthalocyanines and hydrophilic amino acid-derivatized PFPs in vitro and test the most promising candidates in vivo. Although the above studies place great emphasis on demonstrating the efficacy and utility of PFPs as photosensitizers in PDT, quantitation of tissue PFP levels and their subcellular distribution will provide new insight into their mechanisms of action, as well as, relate PFP concentration with dynamic assays of subcellular site-directed effects. We expect that results from these experiments will enable us to establish a PFP-based treatment regimen for PDT that is superior to those used with Photofrin II.
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