Photothermal Sensitization of Biological Systems

在这个新的建议中，研究人员将他们的努力引向生物和模型系统中光热作用的凝聚力研究。该研究将探索光热作用的全部广度，从其物理化学方面到细胞水平和动物水平的表现。主要目的是寻求利用近红外峰值功率激光器和强吸收光敏剂在生物材料中沉积热峰值的影响和后果的机理理解。在第一个具体目标中，研究人员将寻求建立对金属四吡咯大环的分子组成如何影响其激活状态失活的预测性理解。在第二个具体目标下，将研究热峰外热能迁移的动力学以及涉及邻近反应物的假定的能量浪费光化学过程。在具体目标III下，研究小组将研究光热损伤在细胞水平上发生的机制，并确定优化这种光敏化方式效率的因素。需要考虑的问题包括哪些亚细胞位点是敏感的，这些位点如何被靶向，以及光热敏剂的亚细胞分布如何影响导致细胞死亡的途径（例如凋亡与随机坏死）。在Specific Aim IV中，体内系统将被检查。这将需要对肿瘤中增敏剂化合物的积累效率和由此产生的光疗活性进行研究。这里的重要问题是主要和次要细胞/组织目标的性质，以及与辐照点距离的函数的损伤发展。此外，该团队还将研究热冲击波在生物材料中的传播。

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.