切伦科夫辐射激活的组织深部肿瘤治疗方法研究

Cerenkov radiation were extensitively used in molecular imaging because it can be emmited by radionuclids in cells , it also has potential to treat tumors. The combination of light and photosensitizers or antitumor drug for phototherapeutic interventions, such as photodynamic therapy, has transformed medicine and biology. However, the shallow penetration of light into tissues and the reliance on tissue oxygenation to generate cytotoxic radicals have limited the method to superficial or endoscope-accessible lesions. Based on the research that photoresponsive or photosensitizer nanomaterials can be activated by violet light to kill cancer cells, a method is proposed to overcome the limitation of light penetration into the tissue. In this technology, Cerenkov emission induced by radionuclide is used to activate a photoresponsive lipid-polymer hybrid nanoparticle for remotely controlled delivery of anticancer drug-doxorubicin or Ag@titanium dioxide -Hematoporphyrinmonomethyl Ether nanocomposite that accumulated in deep tumorous tissue to kill cancer cells with minimal invasive skill. We will synthesize and optimize these two nanosystems, and then the in vitro and in vivo experiments will be implemented. The spectrum and photon density of Cerenkov radiation in tissue induced by radianuclide were modeled by Frank-Tamm theory and analysed by Monte Carlo Method, which can be combined with single oxigen generation and therapy effects to direct clinical application.

由放射性核素产生的细胞内切伦科夫辐射（CR），在分子成像方面广受关注，也具有治疗肿瘤的潜力。光与光敏剂或抗癌药物结合治疗肿瘤，已得到临床应用或生物学研究，典型的如光动力疗法。但是，由于光对组织的穿透深度有限，且光动力疗效依赖于肿瘤环境中的氧浓度，因此这种方法只能应用于表皮，或必须借助内窥镜系统。本项目以CR能够激活光敏材料为出发点，立足于新型光敏载药体系或光敏剂纳米材料可被紫光激活释药或杀伤肿瘤细胞的研究基础，针对光波难以到达组织深部肿瘤部位的难题，提出利用放射性核素作为辐射源，在组织深部产生CR，以激发累积在肿瘤细胞内的纳光敏米粒子，从而达到微创治疗肿瘤的目的。通过优化制备纳米体系，在细胞实验基础上，进行在体实验。并利用Frank-Tamm理论模型，采用蒙特卡洛算法分析核素在不同组织产生CR的剂量及光子密度，结合单态氧产率理论及光疗效果，建立新模型，为临床治疗提供技术参考。

光与光敏剂或抗癌药物结合治疗肿瘤，已得到临床应用或生物学研究，典型的如光动力疗法。但是，由于光对组织的穿透深度有限，且光动力疗效依赖于肿瘤环境中的氧浓度，因此这种方法只能应用于表皮，或必须借助内窥镜系统。由于可由核素或直线加速器X射线原位产生切伦科夫辐射，在分子成像方面广受关注，也原位治疗肿瘤的潜力。项目提出使用核素与光敏剂结合，或者利用直线加速器对特定的光敏剂进行照射，达到原位治疗肿瘤的目的。主要工作包括：首先制备了分散性好的二氧化钛纳米颗粒，与光敏剂血卟啉单甲醚HMME结合，然后采用直线加速器产生的X射线对结合体进行辐射，检测其单态氧产率；其次，制备了新型的纳米颗粒Ag@TiO2并进行表征，然后利用亚甲基蓝催化级细胞实验对其紫外光（切伦科夫光）辐射效果进行验证；制备了叶酸靶向的PEG-PCL胶束包裹的改性的阿霉素，通过表征，细胞及在体实验，都证明这种纳米胶束在X射线辐射下，能够原位释放药物，并达到肿瘤治疗目的。最后通过色谱及蒙特卡洛模拟计算，进一步证实胶束对X射线的反应是由切伦科夫光引起。