This is a competing continuation proposal requesting support for an experimental research program with the major objective of elucidating the role of singlet molecular oxygen in initiating damage and/or killing of biological systems under photodynamic conditions. Photodynamic effects are important to human health being involved in photoallergic, phototoxic and drug-induced photosensitivity disorders; on the other hand, the use of photoradiation therapy of tumors relies on the photodynamic damage being caused to photosensitizer-doped neoplastic tissue. Photodynamic mechanisms are thought to involve the production of singlet oxygen at an early stage. Knowledge about the behavior of O2(1Deltag) in biological environments and model systems has been sketchy and has been, and continues to be the subject of activity in this laboratory under this grant.
The specific aims are: (i) To continue to pursue investigations into the dynamic properties of O2(1Deltag) in compartmentalized fluid systems such as micro-emulsions, liposomal vesicles and ghost cells. (ii) To characterize the quantitative photoproperties of important sensitizers of O2(1Deltag) such as porphyrins, metallo-porphyrins and xanthenes, with emphasis on environmental effects. (iii) To quantify the production and fate of O2(1Deltag) when formed from sensitizer dyes that are complexed with biopolymers such as proteins and genetic materials. (iv) To investigate the effect of substrate structure and the environment upon the one-electron transfer between O2(1Deltag) and biological reductants such as teh materials in the respiratory and photosynthetic electron transport systems. (v) To examine the yields, lifetimes and reactivities of O2(1Deltag) formed in cultured mammalian cells and to obtain, if possible, direct evidence for its involvement in cell killing, membrane lysis, transport inhibition and so on. These studies will use the physical techniques of laser flash photolysis (nanosecond and picosecond) coupled to optical absorption and emission diagnostics. Infra-red luminescence detection will be principally used for O2(1Deltag) measurements. Cell-killing kinetics will be determined by conventional procedures.
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