复发/转移性肝癌放射性药物筛查-内照射治疗体系的构建

Metastases and postsurgical recurrence are the main causes of hepatocellular carcinoma death, there are limited efficient treatment options for hepatocellular carcinoma. In our previous study, we labeled G-TMTP1 with 18F. We have demonstrated that the probe could specifically target highly metastatic hepatocellular carcinoma. The probe has suitable pharmacokinetic characteristics with fast blood clearance and low liver background. We haven’t seen any reports on therapeutic radiopharmaceutical for metastases and postsurgical recurrence hepatocellular carcinoma. We would validate the target for TMTP1 in vitro and in vivo. We would improve the pharmacokinetics and pharmacodynamics of TMTP1 conjugated with tEB to synthesis PET probe [18F]AlF-NOTA-tEB-TMTP1 and therapeutic radiopharmaceutical 177Lu-NOTA-tEB-TMTP1. Our study will perform on nude mice bearing hepatocellular carcinoma xenogratfs. This study could be further transformed into clinical. We could identify patients with high tumor uptake of [18F]AlF-NOTA-tEB-TMTP1 by PET/CT screening, then we could treat the patients with 177Lu-NOTA-tEB-TMTP1 to achieve truly personalized medicine for the treatment of high aggressive hepatocellular carcinoma. Meanwhile, our strategies could be applied in related research of peptides drug designs.

对于复发和转移性肝癌目前临床上仍然没有有效的治疗方法。我们的前期工作证实18F标记多肽TMTP1可特异性靶向高转移性肝癌，并且在正常肝组织摄取很低。目前尚未见针对复发/转移性肝癌放射性治疗药物的报告。我们提出以TMTP1为靶分子，构建高转移性肝癌的PET诊断探针及放射性治疗药物。本项目拟从细胞和动物水平，验证TMTP1的生物学靶点，并通过tEB偶联TMTP1来延长其血液半衰期，构建PET诊断探针[18F]AlF-NOTA-tEB-TMTP1和放射性治疗药物177Lu-NOTA-tEB-TMTP1。本项目以裸鼠肝癌模型为突破点进行研究，如能成功可进一步转化到临床应用中，其应用策略为，对肝癌复发/转移患者以PET探针进行显像，筛选出特异性摄取TMTP1的病人，然后利用放射性治疗药物进行治疗，最终实现复发/转移性肝癌的个体化治疗。同时，本项目也可为其他多肽分子探针的设计提供新的思路。

对于复发和转移性肝癌目前临床上仍然没有有效的治疗方法。我们的前期工作证实18F标记多肽TMTP1可特异性靶向高转移性肝癌，并且在正常肝组织摄取很低。目前尚未见针对复发/转移性肝癌放射性治疗药物的报告。我们提出以TMTP1为靶分子，构建高转移性肝癌的PET诊断探针及放射性治疗药物。本项目分别通过64Cu和177Lu标记tEB修饰后的多肽TMTP1，合成相应的探针64Cu-DOTA-tEB-TMTP1和177Lu-DOTA-tEB-TMTP1，并进行了体内长循环的显像验证和核素靶向治疗治疗研究，证实我们合成的显像探针64Cu-DOTA-tEB-TMTP1具有体内长循环的效果，核素靶向治疗探针177Lu-DOTA-tEB-TMTP1具有良好肿瘤抑制效果，并且具有良好的临床转化应用前景。本项目资助下已经发表SCI论文三篇，获得授权发明专利一项，并还有一项发明专利在实审中。