靶向肿瘤干细胞治疗肝癌的多模态影像研究

Cancer stem cells (CSCs) are the important cause of the recurrence and metastasis of hepatocellular carcinoma. CD133 and EpCAM are important molecular markers on its surface. The study found that the expression of CD133 and EpCAM liver cancer stem cells have a strong tumorigenicity and drug resistance, resulting in poor treatment of hepatocellular carcinoma. Presumably, the surface molecule CD133 and EpCAM of liver cancer stem cells can be used as targeted treatment sites and the indexes for evaluation. The research uses the synthesis of multifunctional magnetic mesoporous silica composite microspheres loading anti-CD133 and anti-EpCAM molecule targeted drugs and chemotherapy drug of fluorouracil, coupling of anti-CD133 and anti-EpCAM antibodies on it's surface, to make specific targeting CD133 (+) EpCAM (+) CSCs nano-drug for the treatment of hepatocellular carcinoma. While it uses multimodal molecular imaging and functional magnetic resonance imaging technology to monitoring the efficacy. In the final, the pathology results will be used as reference standard. It is to illustrate the effect and mechanism of the treatment of hepatocellular carcinoma by the specific targeting CSCs nano-drug，detect of the CD133 and EpCAM expression to assess the effect of hepatocellular carcinoma. It is to explore the new method for treatment of hepatocellular carcinoma by targeting CD133 (+) EpCAM (+) CSCs. The objective is to improve the curative effect of hepatocellular carcinoma.

肿瘤干细胞(CSCs)是导致肝癌复发、转移的重要原因。CD133及EpCAM是其表面重要分子标记。研究发现表达CD133及EpCAM的肝癌干细胞具有强致瘤性及耐药性，导致肝癌治疗效果差。可以推测，肝癌干细胞表面CD133及EpCAM分子可以作为靶向治疗位点和疗效评价指标。本研究利用前期实验合成的多功能磁性介孔二氧化硅复合微球装载抗CD133和抗EpCAM的分子靶向药物及氟尿嘧定类化疗药物，并在其表面偶联抗CD133及EpCAM抗体，制成能特异性靶向CD133(+)EpCAM(+)CSCs的纳米药物治疗肝癌，同时采用多模态分子影像及磁共振功能成像技术监测疗效，最终以病理结果为参照标准，阐明特异性靶向CSCs的纳米药物在肝癌治疗中的作用和机制，检测CD133和EpCAM表达以评估肝癌疗效，探索靶向CD133(+)EpCAM(+)CSCs治疗肝癌的新方法及疗预后估新指标，达到提高肝癌疗效的目标。

肝癌居全世界肿瘤发病的第五位，致死率高居第三位。肝癌患者手术后或者化疗栓塞治疗后常早期出现复发转移，相关药物也出现耐药以致治疗失败。基于肿瘤干细胞假说，存在以上现象的主要原因是肿瘤组织的异质性，恶性肿瘤依赖其内存在能够致瘤、自我更新、分化及耐药的肿瘤干细胞（cancer stem cells, CSCs）维持肿瘤复发、转移、耐药的病理过程。在国家自然科学基金面上项目基金的资助下，本研究制备多功能磁性介孔二氧化硅纳米颗粒，其核为磁性Fe3O4、外壳为有机介孔二氧化硅层的核-壳结构，可在其孔道内装载化疗药物表阿霉素。采用多功能磁性纳米颗粒对裸鼠皮下移植瘤及兔肝脏原位移植瘤进行治疗，结果表明装载表阿霉素的纳米药物能够下调肝癌肿瘤组织内的CD133等多种肝癌干细胞表面标志物的表达，证实了下调肝癌干细胞具有更好的抗肝癌的效果。并进一步采用纳米药物经动脉灌注治疗，增加了肿瘤局部药物的富集程度，提高了药物的靶向治疗的作用，具有增强抗肿瘤的效果。且治疗后采用近红外荧光及多功能磁共振进行疗效评价，这也为临床肝癌患者的治疗提供了一种新的预后评估指标。总而言之，本研究通过利用抗肝癌干细胞的多功能磁性纳米颗粒达到提高肝癌疗效的目标，且采用多种影像学方法进行疗效评价，为肝癌治疗及疗效评价提供新的思路和方法。