Photodynamic therapy (PDT) utilizing visible light and a non-cytotoxic drug offers a promising alternative treatment for neoplastic tumors, psoriasis and bacterial or viral infections. Damage to intended and non- intended targets may both be at membrane-bound proteins. One focus of the research will be to synthesize a series of known and new photosensitizing drugs based on derivatized phthalocyanines (PCs) which will be amenable to photoactivation in the deep red to take advantage of improved tissue light transmission properties. Two classes of PCs will be made and their photophysical properties characterized: """"""""Type A"""""""" PCs that are polysubstituted with charged groups and thus partition mainly in the aqueous phase, and """"""""Type L"""""""" lipophilic PCs containing long-chain alkyl substituents. A second focus will be to study the solution chemistry and photochemistry of these substituted PCs.
A third aim will be to use bacteriorhodopsin (BR) as a model target for PDT. BR possesses the following advantages as a target protein: (i) It is a well- characterized membrane-bound protein which is readily incorporated into synthetic membranes. (ii) It contains a prosthetic group which is responsible for the characteristic visible absorption and accompanying exciton CD band. Both of these are exquisitely sensitive to changes in the chromophore and/or its binding site. (iii) The fluorescent properties of aromatic residues located in transmembrane segments of the BR polypeptide chain are well characterized and can be utilized to identify conformational changes in the polypeptide. (iv) BR retains its full physiological function as a light-driven proton pump in vitro and thus an assay of this function can be used as an additional standard for photodynamic damage. In the proposed project the photodynamic effects of these compounds on BR incorporated into synthetic liposomes will be measured with the aim of distinguishing effects due to the initial location of photogenerated species resulting from the solubility properties of the sensitizers and the orientation of BR in liposome membrane. The project will expose students preparing for careers in biomedical research to a wide range of physicochemical, biochemical and synthetic techniques in a study of the design and function of new chemotherapeutic drugs for the treatment of neoplastic tumors and infections.
