内照射与化疗协同兼具多模态影像监测功能的诊疗剂用于肝脏VX2瘤经动脉介入治疗的研究

As the main treatment for liver tumor that lack of the possibility of excision, clinical effect of transarterial chemoembolization (TACE) should be improved, where the controlled-releasing drugs and chemoradiotherapy may have the promising values. Based on the previous research on dual-modal imaging and sensitized radiotherapy, BaGdF5@CDDP@SiO2(188Re-Sn) was designed and developed as theranostics with the ability of controlled release, chemoradiotherapy, and multimodal imaging monitoring. In this research, rabbits models with VX2 liver tumor were randomly divided and treated via transarterial interventional embolization: control group (normal saline), research group I (iodipin + CDDP), research group II (iodipin + CDDP controlled-releasing drugs), research group III (iodipin + Re-188 labeled Sn colloids), research group IV (iodipin + Re-188 labeled functional particles), and research group V (iodipin + Re-188 labeled & CDDP controlled-releasing drugs). Pathological findings were set as gold standard, and comparisons among groups and between pre- and post-treatments were performed to make a comprehensive evaluation on the advantages of chemoradiotherapy, to explore the influence of therapeutic factors on tumor angiogenesis, hypoxia-inducible factor and cellular apoptosis. Bio-safety of theranostics was evaluated based on the therapeutic effects and blood test results. Overall, this research aims to improve the curative effect of interventional treatment of liver cancer, and provide valuable guide for the clinical translation of multi-functional theranostics.

TACE是不能手术切除肝癌的主要治疗方法，临床疗效亟需提高，其方法包括缓释化疗药物、结合放射治疗等。我们在前期开展双模态成像及放疗增敏研究的基础上，设计集核素内照射与化疗药物缓释协同、多模态影像监测于一体的多功能诊疗剂BaGaF5@CDDP@SiO2(188Re-Sn)。利用兔肝脏VX2瘤模型，分组经导管肝动脉栓塞给药：对照组（生理盐水）、组Ⅰ（碘油+顺铂）、组Ⅱ(碘油+顺铂缓释材料)、组Ⅲ（碘油+Re-188-Sn胶体）、组IV（碘油+Re-188标记功能材料）、组V（碘油+Re-188标记的顺铂缓释材料）。以病理为金标准，通过组间及治疗前后自身比较，综合评价诊疗剂的内照射与缓释化疗药物的协同优势、多模态影像监测的优势，探讨治疗因素对肿瘤新生血管生成、乏氧诱导因子及细胞凋亡的影响；结合血液指标检测结果，评价诊疗剂的生物安全性。为提高肝癌介入治疗效果及多功能诊疗剂的临床转化提供参考。

经肝动脉化疗栓塞（TACE）是中晚期肝细胞肝癌的常用治疗方法，能够阻断肿瘤供血动脉，并实现肿瘤部位高浓度药物化疗。尽管TACE具有确定疗效，但总的有效率及长期疗效不够理想。同样基于肝动脉栓塞治疗手段，肝动脉放疗栓塞（TARE）技术则通过栓塞及局部核素内照射达到治疗肝癌的效能。使用纳米材料装载化疗药和治疗性核素能够在栓塞的基础上同时实现药物化疗与核素内放疗联合治疗，有望为解决目前肝癌治疗困境提供新的思路和方案。.本课题设计了一种具有栓塞局部药物缓释化疗、核素选择性内照射放疗、CT/MRI/SPECT显像性能的多功能纳米诊疗剂BaGdF5@CDDP@SiO2(188Re-Sn)，并对其进行细胞毒性研究；主要采用兔肝VX2 瘤模型进行多组别介入栓塞治疗活体实验，部分分组对照研究基于大鼠N1S1肝癌模型。通过PET/CT评价TACE与TARE联合治疗协同效果，SPECT/CT显影材料生物分布，MRI观察诊疗剂增强效果，通过组织标本及血液进行治疗安全性评估。.采用氧化硅包覆法成功合成了BaGdF5@CDDP@SiO2(188Re-Sn)，粒径约120 nm，实现188Re标记以及顺铂负载、缓释。CCK-8细胞实验结果验证了该材料对肝癌细胞具有良好治疗效果。治疗后肝癌18F-FDG PET/CT显像提示BaGdF5@SiO2@CDDP(188Re-Sn) 即协同治疗组治疗效果优于单模式治疗组，SPECT/CT显示纳米材料主要分布于肿瘤部位，可实现稳定持续性内照射治疗。制备兔肝VX2肿瘤模型并实现多组别介入治疗，影像以及TUNEL染色结果再次验证放化疗协同治疗优势，MRI显像结果显示纳米材料具有一定的T1WI增强效果，主要器官H&E染色以及血液肝肾功指标结果显示该放化疗协同纳米诊疗剂用于肝癌治疗的生物安全性好。本研究为开发肝癌介入治疗新型多功能微球等新材料提供了参考和借鉴。