Photothermal Sensitization of Biological Systems

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In this new proposal, the investigators direct their efforts towards a cohesive study of photothermal action in biological and model systems. The investigation will explore the full breadth of photothermal action from its physicochemical aspects to the cell-level and animal-level manifestations. The primary objective is to seek mechanistic understanding of the effects and ramifications of depositing heat spikes in biological material using near-IR high-peak-power lasers and strongly absorbing photosensitizing agents. In the first Specific Aim the investigators will seek to establish a predictive understanding of how the molecular composition of the metallotetrapyrrole macrocycles influences the deactivation of their exited states. Under the second Specific Aim a study will be made of the dynamics of thermal energy migration out of the heat spike and of putative energy-wasting photochemical processes involving proximately situated reactant species. Under Specific Aim III the team will examine the mechanisms through which photothermal damage occurs at the cellular level and to define the factors which optimize the efficiency of such a photosensitization modality. Among questions to be considered are which sub-cellular sites are sensitive, how such sites can be targeted, and how the sub-cellular distribution of the photothermal sensitizers can influence the pathways (e.g. apoptosis vs. random necrosis) leading to cell death. In Specific Aim IV in vivo systems will be examined. This will entail a study of the efficiency of accumulation of sensitizer compounds in tumors and the resulting phototherapeutic activity. Important issues here are the nature of the primary and secondary cell/tissue targets, and the development of damage as a function of the distance from the irradiation site. In addition the team will investigate the propagation of thermal shock waves in biological materials.