Design and evaluation of DNA photocleaving agents for bioinorganic applications

DNA光裂解剂是一种能够在DNA主干上诱导单链或双链断裂的分子。光激活后裂解DNA的分子在光动力疗法(PDT)中具有重要意义，这一策略已被应用于某些癌症、血管内疾病和老年性黄斑变性的成功治疗。简而言之，PDT使用了一种有机光敏剂，在可见光照射下会产生有毒的氧物种。不幸的是，有机光敏剂依赖于氧的存在来发挥作用，不能被组织最透明的波长的光激活。因此，PDT在治疗深层或缺氧组织方面无效，这些组织包括一些最恶性和耐药的肿瘤。这项建议概述了一项研究计划，该计划致力于通过引入过渡金属络合物作为无机PDT的光敏剂来克服这些限制。这项提议将确定在近红外光激活时破坏DNA并且不需要氧气来发挥作用的无机系统。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定的区域引起最大损害。

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.