基于DNA纳米结构的新型核医学探针用于抑制顺铂肾毒性的机制与作用研究

顺铂是多种肿瘤的一线化疗用药，但其肾毒性是限制化疗功效的主要因素。顺铂分子在肾脏排泄过程中可直接损伤肾小管细胞DNA，并上调肾脏氧化应激水平间接侵害肾功能。因此，于肾脏原位捕获顺铂分子并清除活性氧自由基（ROS）有望抑制顺铂的双重毒性。申请人前期研究发现合理构建的DNA纳米结构在体内具有专一的肾脏靶向能力，故而DNA纳米结构有望作为外源DNA，实现顺铂分子的肾脏直接捕获，而DNA的天然还原性有望用于ROS清除。本项目拟设计构建DNA纳米结构，通过Ga-68的放射性标记构建DNA纳米核医学探针，在核医学影像指导下得到具有高效肾脏靶向的DNA纳米探针，在细胞和动物水平验证DNA纳米药物捕获顺铂分子和清除活性氧的效率与机制，并在肺癌小鼠模型中探索顺铂用药后DNA纳米药物对其肾毒性的抑制效果以及作用机制。基于DNA纳米结构的新型核医学探针有望抑制顺铂双重肾毒性，最大化顺铂的抗肿瘤功效。

Cisplatin is the first-line chemotherapy drug for many types of tumors, but its nephrotoxicity is the main factor limiting the efficacy of chemotherapy. Cisplatin molecules can directly damage the DNA of renal tubular cells in the process of their renal excretion, and up-regulate the level of oxidative stress in the kidneys to induce indirect injury of renal function. Therefore, capturing cisplatin molecules in situ in the kidney and scavenging reactive oxygen radicals (ROS) is expected to inhibit the dual toxicity of cisplatin. The applicant’s previous research found that reasonably constructed DNA nanostructures have specific kidney targeting ability in living organisms. Therefore, DNA nanostructures are expected to be used as exogenous DNA to achieve direct capture of cisplatin molecules in the kidneys, and the natural antioxidant properties of DNA are expected to be used for removal of excessive ROS. This project aims to design DNA nanostructures, construct DNA nanostructure-based nuclear imaging probes via Ga-68 radiolabeling, obtain DNA nanoprobes with specific renal accumulation under the guidance of nuclear imaging, and verify the mechanism and efficacy of cisplatin capture and ROS scavenging at the cellular and animal level. We intend to explore the inhibitory effect and mechanism of action of DNA nanomedicine on the nephrotoxicity of cisplatin after cisplatin administration in murine models of lung cancer. Novel nuclear medicine probes based on DNA nanostructures are expected to inhibit the dual nephrotoxicity of cisplatin and maximize its anti-tumor efficacy of cisplatin chemotherapy.