131I-金丝桃素靶向坏死肿瘤清除肝癌动脉栓塞后残留病灶及其机制研究

Hepatic artery embolization is the preferred treatment for inoperable liver cancer. However, tumor recurrence due to residual lesion after hepatic artery embolization is often unavoidable. Embolization combined targeted radiation therapy is a new strategy to eradicate residual tumor. Necrotic targeted radiation therapy, targeting tumor necrosis tissue, has the advantage of high specificity and weak heterogeneity. It is expected to become the preferred method that combined embolization for the treatment of liver cancer. Previously, we found that radioiodinated hypericin (131I-Hyp) could target tumor necrotic tissue and inhibit the growth of residual tumor after chemotherapy. Hepatic artery embolization, caused a large number of tumor necrotic tissue, can be used as the ideal drug targets. Therefore, we speculate that a combined targeted therapy based on hepatic artery embolization combined necrotic targeted treatment could be a new efficient strategy for the treatment of liver cancer. This project aims to prepare radiopharmaceuticals, establish the model of liver cancer on rabbit, and investigate the targetability and therapeutic effect of the radiopharmaceutical applied in two combined therapies, i.e. hepatic artery embolization plus intravenous injection of 131I-Hyp or hepatic artery embolization using iodized mixed with 131I-Hyp. Finally, we will also explore whether these bianthraquinones target necrotic tissues by preferentially embedding into DNA. This study will provide the new ideas and scientific evidence for combined therapy of residual tumor after hepatic artery embolization.

肝动脉栓塞是肝癌非手术治疗的首选方法，但栓塞后病灶残留是其复发的主要原因。使用放射性药物协同栓塞可清除残留病灶，是提高其疗效的新治疗策略。坏死靶向放射性药物以肿瘤坏死组织为靶，具有靶标特异性高且异质性弱的优点，有望成为联合栓塞治疗肝癌的优选方案。我们前期发现了高效的小分子坏死靶向性药物131I-金丝桃素(131I Hyp)，并证明其能显著提高化疗效果。考虑到肝癌栓塞后造成大量坏死组织，可作为该类药物的理想靶标，因此我们推测，肝动脉栓塞联合坏死靶向治疗是一种高效互补的肝癌治疗新方案。故本项目拟制备放射性药物，在兔肝癌模型上分别采用栓塞后静脉注射131I Hyp，及碘油混合131I Hyp的肝动脉栓塞两种方式治疗，探讨其放药靶向规律及治疗效果，并深入阐述131I Hyp是否通过与坏死组织暴露的DNA嵌合而实现靶向作用的机制。本研究将为肝动脉栓塞后残余肿瘤的联合治疗提供新思路和科学依据。

肝动脉栓塞术是肝癌非手术治疗的首选方法，但栓塞后病灶残留是其复发的主要原因。肿瘤坏死靶向放射性药物以坏死组织为靶，具有靶标丰富且异质性小的优点。考虑到肝动脉栓塞后会造成肝脏肿瘤因缺血而出现大量坏死，因此，肝动脉栓塞术联合坏死靶向放射性药物有望成为一种高效互补的肝癌治疗新策略。本项目首次评价了坏死靶向放射性药物131I-金丝桃素(131I-Hyp)在兔VX2肝癌模型上经静脉注射和与碘油混合肝动脉栓塞给药两种不同给药方式的药代动力学特征，分别测定和评估了肝动脉栓塞后联合131I-Hyp序贯治疗和碘油混合131I-Hyp放射性栓塞治疗两种联合治疗方式中131I-Hyp的分布规律和辐射计量学，并在兔VX2肝癌模型上分别考察了两种不同联合方式的治疗效果，此外还深入探究了131I-Hyp是否通过与坏死暴露的DNA嵌插结合而实现坏死靶向的机制。本项目研究发现131I-Hyp在肝动脉栓塞后联合131I-Hyp序贯治疗和碘油混合131I-Hyp放射性栓塞治疗两种联合治疗方式中的血浆半衰期分别为19.81±3.90 h和14.71±7.29 h。在两种不同联合治疗方式中，131I-Hyp均表现出最高的坏死肿瘤摄取，较低的正常组织分布；与肝动脉栓塞后联合131I-Hyp序贯治疗方式相比，碘油混合131I-Hyp放射性栓塞治疗方式中131I-Hyp表现出更高的肿瘤摄取；肝动脉栓塞联合131I-Hyp对兔VX2肝癌的治疗效果均优于单独肝动脉栓塞治疗的效果，且碘油混合131I-Hyp栓塞治疗比肝动脉栓塞后联合131I-Hyp序贯治疗显示出更优的治疗效果。机制研究表明，131I-Hyp的坏死亲和性主要归因于其与坏死细胞暴露DNA的嵌插结合。本项目研究发现为肝动脉栓塞后残余肿瘤的治疗提供了新的联合策略和科学依据。