新型64Cu标记稀土切伦科夫光动力凝胶微球用于肝癌栓塞联合治疗研究

肝癌是临床常见恶性肿瘤，介入栓塞化疗已广泛用于肝癌临床治疗但常遇耐药瓶颈。以核素切伦科夫辐射（CR）为光源的自激发光动力疗法（PDT）有望联合介入栓塞突破传统疗法瓶颈，但CR较低的发光强度已成为限制该疗法发展的关键。基于课题组前期在核壳稀土纳米晶发光增强、稀土发光能量传递机制和PDT抗肿瘤治疗方面的研究基础，本项目拟通过对高原子序数Lu掺杂核壳稀土纳米晶进一步标记核素64Cu，提出一种基于双辐射（CR和β辐射）增强型PDT凝胶微球的肝癌介入栓塞治疗新策略：1）研究核素CR和β辐射对Lu掺杂核壳稀土纳米晶的发光增强机制；2）以pH响应型聚合物水凝胶为载体制备具有自激发PDT抗肿瘤活性的凝胶栓塞微球，阐明微球辐射增强活性氧产生和细胞损伤机制；3）开展自激发PDT凝胶微球用于兔VX2肝癌的介入栓塞疗效机制研究。本项目有望为放射性核素自激发PDT用于肝癌等深部肿瘤的治疗研究提供科学依据和理论支持。

Hepatocellular carcinoma (HCC) is a common clinical malignancy. Transcatheter arterial chemoembolization (TACE) has been widely used in the clinical treatment of HCC, but drug resistance remains the main challenge. Photodynamic therapy (PDT) with Cherenkov radiation (CR) as the endogenous light source is expected to break through the bottleneck of traditional treatment in combination with interventional embolization. Still, the low photon production yield of CR has become a key factor restricting the development of this new type of PDT. Therefore, strategies to amplify the therapeutic effect of CR-induced PDT are urgently needed. Based on the preliminary researches of luminescence enhancement in lanthanide‐doped core–shell upconversion nanocrystals, energy transfer mechanism of lanthanide‐doped core–shell nanoarchitectures and PDT induced-HepG2 cell apoptosis, we designed a new type of pH-responsive hydrogel embolization microsphere based on 64Cu-labeled high-Z Lu-doped core-shell nanoarchitecture for efficient interventional embolization of HCC. Through the mechanism analysis of the interaction and energy transfer between CR, β radiation of radionuclides, and high-Z Lu-doped core-shell nanocrystal, we will provide the theoretical support for designing self-stimulated PDT hydrogel embolization microspheres with high ROS generation ability and biocompatibility for deep cancer treatment. Meanwhile, the anti-tumor effect of self-stimulated PDT hydrogel embolization microspheres will be investigated at the cell level and in the subcutaneous tumor model of mice. Finally, the therapeutic evaluation and mechanism study of 64Cu-labeled self-stimulated PDT hydrogel embolization microspheres in interventional embolization of rabbit VX2 liver cancer will be carried out under PET-CT guidance. The implementation of this project is expected to provide new ideas and scientific basis for radionuclide self-stimulated PDT in the treatment of HCC or other deep tumors.