硝基咪唑与IR-780的共价连接及其肿瘤靶向放疗增敏作用的实验研究

Hypoxia is a critical factor to bring unsatisfactory outcomes in radiotherapy of cancer patients. Nitroimidazoles have exhibited a promsing prospect as effective radiosensitizers based on hypoxia in tumor therapy, however, few of them has been approved to use in clinic because of their low tumor specificity and severe side-effects during the treatment. In our previous research, we firstly reported IR-780, a small organic molecular with simultaneous tumor-specific accumulation and near-infrared (NIR) imaging properties in a verisity of tumor cells and xenograft models. Based on this finding, we conceive a design that conjugation of nitroimidazoles into the structure of IR-780, aiming to improve its tumor-selective distribution and the tumor radiosensitization. In order to testify this hypothesis, we will firstly carry out a rational design to synthesize a variety of nitroimidazole derivatives substituted by different groups with different eletrophilicity and lipophicity in its parental structure, because the radiosensitive effect has been approved to relate to its eletrophilicity and lipophicity. Meanwhile, the synthesis of different nitroimidazole derivatives with various reactive moieties also facilites them to conjugate with IR-780. Then, the newly synthesized nitroimidazole derivatives are designed to covalently conjugate to different positions of IR-780. Finally, their tumor-targeted radiosensitization are investigated both in vitro and in vivo models, to obtain a new class of nitroimidazole derivatives with the multifunctional properties of tumor-targeted imaging and radiosensitzation, and obtain the preliminary cules of their structure-activity relationship . This project is prospected to explore a novel strategy and provide a theoretical basis for tumor-targeted radiosensitzation.

缺氧是造成肿瘤放疗效果欠佳的重要原因。硝基咪唑类化合物是一类针对缺氧的放射增敏剂，然而由于其对肿瘤组织选择性不理想，临床应用中常因严重毒副作用而受到限制。申请人课题组前期首次报道了一个同时具有肿瘤靶向、近红外荧光显影特性的有机小分子IR-780，其优异的肿瘤选择性在多种肿瘤细胞及荷瘤动物模型中得到验证。在此基础上本项目提出，将硝基咪唑与IR-780共价连接后，可望增强并示踪其在肿瘤部位的选择性分布，从而提高靶向放疗增敏作用。鉴于不同亲电性、亲脂性的硝基咪唑类似物与IR-780化学连接，会直接影响放疗增敏作用以及肿瘤靶向特异性，本项目拟首先通过对硝基咪唑进行各种亲电性、亲脂性的化学修饰，同时引入可供反应的活性官能团，然后与IR-780进行共价连接，最后通过体内外实验研究，筛选具有肿瘤靶向放射增敏作用的新型硝基咪唑类放疗增敏剂，并获得初步构效关系，为肿瘤放疗增敏探索新的靶向策略和理论依据。

硝基咪唑类化合物是一类针对缺氧的放射增敏剂，然而由于其对肿瘤组织选择性不理想，临床应用中常因严重毒副作用而受到限制。申请人课题组前期首次报道了一个同时具有肿瘤靶向、近红外荧光显影特性的有机小分子IR-780，其优异的肿瘤选择性在多种肿瘤细胞及荷瘤动物模型中得到验证。在此基础上本项目提出，将硝基咪唑与IR-780共价连接后，可望增强并示踪其在肿瘤部位的选择性分布，从而提高靶向放疗增敏作用。鉴于不同亲电性、亲脂性的硝基咪唑类似物与IR-780化学连接，会直接影响放疗增敏作用以及肿瘤靶向特异性，本项目首先通过对硝基咪唑进行各种亲电性、亲脂性的化学修饰，同时引入可供反应的活性官能团，然后与IR-780进行共价连接，最后通过体内外实验研究，筛选具有肿瘤靶向放射增敏作用的新型硝基咪唑类放疗增敏剂，并获得初步构效关系，为肿瘤放疗增敏探索新的靶向策略和理论依据。