Photothermal Sensitization of Biological Systems

在这项新的提案中，研究人员将他们的努力指向对生物和模型系统中光热作用的一致研究。这项研究将探索光热作用的全范围，从其物理化学方面到细胞水平和动物水平的表现。主要目标是寻求对使用近红外高峰值功率激光和强吸收光敏剂在生物材料中沉积热峰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一种预测性的理解，即金属四吡咯大环的分子组成如何影响其激发态的失活。在第二个具体目标下，将研究热能从热峰向外迁移的动力学，以及涉及邻近反应物物种的假定的浪费能量的光化学过程。在特定目标III下，该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模式的效率的因素。需要考虑的问题包括哪些亚细胞部位是敏感的，这些部位如何被靶向，以及光热增敏剂的亚细胞分布如何影响导致细胞死亡的途径(例如，凋亡和随机坏死)。在特定的目的IV体内系统将被检查。这将需要研究增敏剂化合物在肿瘤中积累的效率和由此产生的光疗活性。这里的重要问题是初级和次级细胞/组织靶的性质，以及损伤的发展作为离照射地点的距离的函数。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.