以肝癌干细胞为靶标的多模态成像导航在肝癌介入治疗的研究

The recurrence of hepatocellular carcinoma (HCC) after interventional therapy is a tough clinic problem. Liver cancer stem cells (LCSC) are responsible for HCC recurrence. Therefore, efficient detection and eradication of LCSC is critical for the prevention of HCC recurrence. This proposal will focus calcium channel α2δ1-Ⅴ (CCα2δ1-Ⅴ), a specific surface molecule of LCSC, as target, and design and fabricate PET/MR multi-modality imaging probes. The localization and the number of LCSC in HCC could be sensitively and accurately evaluated by the integration of PET and MR imaging. Moreover, we will construct LCSC-targeted intelligent nano-drug. On the basis of the navigation of LCSC-targeted molecular imaging, we can deliver the nano-drug into HCC tissue through catheter. Dual-targeted and accurate therapy for HCC could be accomplished through combining the target effect on both hepatocellular carcinoma cells and LCSC. LCSC-targeted multi-modality imaging navigation system set up in this project will provide theoretical basis and scientific foundation to the establishment of accurate and personalized HCC interventional therapy plan and real-time and effective evaluation of therapeutic efficacy. The LCSC-targeted nano-drug developed in this platform will potentially cure HCC radically and prolong patient survival duration.

介入术后肝细胞肝癌（HCC）复发是临床治疗的难题，而肝癌干细胞（LCSC）是HCC复发的根源。因此，有效发现并杀死LCSC是预防HCC复发的关键。本课题拟以LCSC的特异表面标志Ⅴ型钙通道α2δ1（CCα2δ1-Ⅴ）为靶点，制备高性能的PET/MR多模态分子影像探针，将PET成像与MR成像相结合，以期实现对LCSC分布位置的灵敏准确定位以及其数量的评估；在实现以LCSC为靶标的分子影像导航基础上，构建LCSC靶向的高性能智能纳米药物，经导管定向输送到肝癌组织，以期实现对肝癌细胞和LCSC的双靶向精准治疗。本项目建立的LCSC靶向多模态影像导航系统，为制定精准和个体化的HCC介入治疗方案，以及实时有效评估治疗效果提供理论基础和科学依据；在此平台所开发的LCSC靶向纳米药物，有望“根治”HCC，提高患者的生存期。

有效发现并杀死肝癌干细胞（LCSC）是预防肝细胞肝癌复发的关键。本项目使用活细胞指数富集配体系统进化技术（CELL-SELEX），筛选出识别LCSC（CD133+）的5条候选核酸适配体；细胞和肝癌动物模型结果表明，5号适配体（A5）对肝癌细胞具有特异靶向性；临床组织学检测结果显示，A5对预后差、恶性程度高的肝癌组织的结合更强。以上细胞-动物-临床三个层面的结果证实了适配体A5能够特异识别LCSC，具有肝癌组织结合的靶向性，能够为肝癌的诊断和治疗提供重要的载体。系统研究了磁性颗粒的组成成分和表界面结构与其磁共振T1和T2造影能力的构效关系，通过构效关系理性设计合成了高性能T1明场造影剂、高性能T2暗场造影剂、T1-T2双模式磁共振造影剂和可激活的磁共振成像探针等，用于原位肝癌等肿瘤模型的灵敏特异成像。发展了简便合成砷剂纳米药物的策略，实现了载药量高且重复性好的优点，并有望进一步合成放大；砷剂纳米药物可增加药物摄取量，并降低毒副作用，并且在体内外实验证实了，砷剂纳米药物通过调节SHP-1/JAK2/STAT3 通路抑制肝癌细胞干性和上皮间质转化（EMT）发挥抗肿瘤的作用；设计合成了一类具有pH响应的砷剂纳米药物，纳米药物在酸性条件下水解释放出Mn2+和砷，从而实现了触发式T1明场造影成像，实现了活体下实时监测砷剂药物的释放情况。以上研究成果为LCSC靶向的成像和治疗提供了新思路。