生物可利用硒代半胱氨酸基纳米放疗增敏剂的构建及其对肝癌的放疗/热疗增敏研究

Radiotherapy (RT) remains a cornerstone of cancer administration to date. Moreover, tumor cells can produce resistance to ionizing radiation and cause unavoidable collateral damage to surrounding normal tissue. Recently, multifunctional nanomaterials as radiosensitizers have attracted much interest in RT of cancer. However, these reports mostly focus on the nanoparticle-mediated radiotherapeutic enhancement, and few studies concern on how to reduce the radiation side-effects and potential long-term toxicity. The development of new generation of nanoscaled radiosensitizer that can not only enhance radio-sensitization of the tumor tissue, but also increase radio-resistance of the healthy tissue is highly desirable, but remains a big challenge. In this study, we will design a new versatile theranostics based on endothelial growth factor (EGF) modified selenocysteine-FeSe2 nanoparticles for simultaneously enhancing radio-photothermal therapeutic effects and reducing the side-effect of radiation. Based on the biodegradability and utilization of Se/Fe element, the nanoparticles could overcome metal toxicity when gathered in the vital organs. The nanoparticles could accumulate in the cancer cells due to the modified target by EGF. The as-prepared nanoparticles will exhibit significantly enhanced free radical generation upon X-ray radiation and remarkable photothermal effects under 808 nm NIR laser irradiation which could improve the blood oxygen content of the tumor tissue based on the precise localization of tumor boundaries by MRI, CT and photoacoustic multimode imaging. In addition, with combination of in vivo and in vitro studies, the radiosensitive effect and mechanism of nanoparticles is explored. Moreover, these nanoparticles are biodegradable. The appropriate amount of selenium and iron elements could strengthen the immune function and reduce the side-effects of radiation in whole body because selenium can be incorporated into protein, iron can be participate in the synthesis of hemoglobin, and promoting secretion of cytokines. The successful implementation of this project will provide the theoretical and experimental basis which in improve the radio-therapeutic effect of advanced liver cancer.

放疗在肝癌治疗中占有重要地位，但其治疗效果不佳且易产生毒副作用。已有纳米放疗增敏剂可增强放射线对肿瘤的治疗效果，但无法改善放射线对机体造成的毒副作用，且具有潜在长期毒性。本项目拟利用硒与铁元素可生物降解利用特性，以温和热解法构建一种结合热疗既可对肿瘤组织放疗增敏，又可降低放疗对正常组织带来毒副作用的表皮生长因子修饰的硒代半胱氨酸基纳米放疗增敏剂。该纳米放疗增敏剂可实现与肝癌细胞的靶向结合，并可生物降解利用，结合热疗可实现放疗对肝癌细胞的增敏杀伤；利用其可作为MRI、CT和光声多模态成像对比剂的特性，可实现对肿瘤边界的精准定位。进一步的将在体内外系统研究该纳米放疗增敏剂的增敏效果及增敏机制；利用降解后硒和铁元素参与硒酶、血红蛋白合成，刺激细胞免疫因子释放的能力，研究其显著改善放射线对机体产生的毒副作用的机理。本项目的顺利实施将为扩大放疗在临床中、晚期肝癌中的精准治疗奠定相关的理论和实验基础。

放疗/微波消融在肝癌治疗中占有重要地位，但其治疗效果不佳且易产生毒副作用。已有纳米放疗增敏剂/微波增敏剂可增强放射线/微波对肿瘤的治疗效果，但无法改善放射线/微波对机体造成的毒副作用，且具有潜在长期毒性。本项目通过设计构建一系列的纳米放疗增敏剂和微波增敏剂，联合放射线或微波消融实现了对肿瘤细胞的精准杀伤，并利用纳米材料自身的特性有效降低了放射线或微波热对肿瘤毗邻正常组织的辐射损伤或热损伤。同时，本项目通过利用临床中普遍使用的经肿瘤供血动脉灌注化疗药物的方式，实现了纳米材料在肿瘤部位的高度富集，降低了纳米材料在正常组织器官的分布及其带来的潜在毒副作用。通过利用纳米放疗增敏剂治疗平台，实现了放疗诱导的抗肿瘤免疫功能增强，既可对原位肿瘤进行有效杀伤，还有效抑制了肿瘤的复发和转移。同时，利用纳米材料具有CT成像和光声成像的功能，我们实现了对肿瘤边界的精准定位，使得放射线或微波热照射肿瘤时能够更加精准。在该项目的支持下，课题组共发表高水平研究论文3篇，其中影响因子大于15的2篇、大于10的1篇，获得山西自然科学奖二等奖1项（排名第一），申请国家发明专利1项。通过本项目的实施，为未来临床放疗和微波消融联合纳米增敏剂在治疗中、晚期肝癌中的应用奠定了坚实的理论和实验基础。