Design and evaluation of DNA photocleaving agents for bioinorganic applications

DNA光切分剂是能够在DNA主干中诱导单链或双链断裂的分子。在光激活下切割DNA的分子在光动力治疗（PDT）中具有重要意义，这种策略已成功应用于光动力治疗某些癌症、血管内疾病和年龄相关性黄斑变性。简单地说，PDT采用一种有机光敏剂，在可见光照射下产生有毒的氧。不幸的是，有机光敏剂依赖于氧气的存在来发挥作用，不能被组织最透明的光波长激活。因此，PDT对深层或缺氧组织无效，其中包括一些最恶性和耐药的肿瘤。本提案概述了一个研究计划，致力于通过引入过渡金属配合物作为无机PDT的光敏剂来克服这些限制。该提案将确定在近红外光激活时破坏DNA的无机系统，并且不需要氧气即可发挥作用。由于DNA是所有细胞功能的蓝图，针对遗传机制的新型光敏剂将在预先选择的区域引起最大的损伤。

DNA photocleaving agents are molecules capable of inducing single- or double-strand breaks in the DNA backbone. Molecules that cleave DNA upon activation with light are of significant interest for use in photodynamic therapy (PDT), a strategy that has been applied to the successful treatment of certain cancers, intravascular disease, and age-related macular degeneration. Briefly, PDT employs an organic photosensitizer that generates toxic oxygen species upon irradition with visible light. Unfortunately, organic photosensitizers rely on the presence of oxygen to function and cannot be activated by wavelengths of light where tissue is most transparent. Therefore, PDT is not effective in treating deep or hypoxic tissue, which comprises some of the most malignant and drug-resistant tumours. This proposal outlines a research plan that is devoted to overcoming such limitations by introducing transition metal complexes as photosensitizers for inorganic PDT. This proposal will identify inorganic systems that damage DNA when activated by near-IR light and do not require oxygen to function. Since DNA is the blueprint for all cellular function, new photosensitizers that target the genetic machinery will elicit maximal damage in a pre-selected area.