基于纳米二氧化锆药物控释系统的肝癌靶向介入治疗及其治疗响应的多模态影像学监测研究

Hepatocellular carcinoma (HCC) is one of the most malignant tumors which do harm to human health seriously. At present, the drug therapy is not satisfactory because of its systemic toxicity and lack of targets. In this study, we construct the new targeting drug control release system for HCC with multi-shell nano hollow mesoporous ZrO2 ball, loading specific cytotoxic drugs in the space between the shells. To reach the maximum tumor-killing effect and reducing the systemic side effects, the programmed targeting therapy of HCC will be achieved by interventional approach directly to tumor feeding artery, enhanced permeability and retention (EPR) effect of inorganic nano material in tumor, modification with active targeting molecules to deliver the specific drugs to the sensitive organelles, and control by intelligent thermal trigger switch. It is proposed by using the multimodal imaging methods for evaluation of the efficacy of local tumor drug concentration and treatment efficacy. Tumor response will be monitored by spectral CT, MRI and SPECT-CT based on necrosis-targeted 131I-hypericin. Through this study it is planned to find new ways of targeting chemotherapy, to establish an efficient method for monitoring targeting treatment strategies, to improve the efficacy of drug therapy, and to prolong the survival of patients with HCC.

肝癌是严重影响人类健康的恶性肿瘤之一，目前的药物治疗因全身毒副作用大和缺乏靶向性而疗效不佳。本研究针对肝癌药物治疗靶向性差和疗效响应监测缺失等临床问题，以纳米多壳介孔中空二氧化锆球为核心材料，利用其多壳间的空间装载纳米影像探针与特异性细胞毒性化疗药物，表面偶联靶向分子与智能开关，构建新型药物控释系统。利用肿瘤供血动脉介入途径给药、无机纳米材料的肿瘤EPR效应、材料表面主动靶向分子修饰、材料热触发智能开关控制实现肝癌程序性靶向治疗，将特异性细胞毒性药物直接输送至敏感细胞器，达到最大限度的杀伤肿瘤和降低全身毒副作用的目的。拟通过能谱CT、MRI和基于碘131-金丝桃素坏死靶向SPECT的多模态成像方法进行肿瘤局部药物浓度监测、治疗早期和晚期的疗效评价，进行全面的治疗响应监测。以期通过本研究开辟肝癌靶向化疗的新途径，建立一套高效的肝癌靶向治疗策略和疗效响应监测方法，提高肝癌患者药物治疗的疗效。

肝癌是严重影响人类健康的恶性肿瘤之一，但由于肝癌的发病隐匿，进展较快，大多数患者在临床确诊时就已经是中晚期，从而失去了手术治疗的机会。因此，因此，以肝动脉化疗栓塞术（TACE）为主的介入微创治疗就成为了此类肝癌患者的主要治疗手段。然而，目前的介入治疗一直因没有疗效明确的化疗药物，而且毒副作用大和缺乏靶向性而疗效不佳。本研究针对肝癌药物治疗靶向性差和疗效响应监测缺失等临床问题，以纳米介孔中空二氧化球为载体，以三氧化二砷和阿霉素作为主要化疗药物，并研究了多种靶向治疗手段，包括在其表面修饰靶分子TPP、iRGD肽，利用仿生工程手段修饰红细胞膜提高了二氧化锆在肿瘤部位的蓄积，以及在其内部装载液态金属，将其转变为柔软的二氧化锆球促进其在肿瘤部位的内吞等，构建了系列新型药物控释系统，用于有效克服抗肿瘤药物治疗靶向性差等问题，同时通过能谱CT、MRI和基于碘131-金丝桃素坏死靶向SPECT的多模态成像方法对肿瘤局部药物浓度监测、治疗早期和晚期的疗效评价，实现全面的治疗响应监测。是从根本上改变肿瘤（原发性肝癌）治疗模式的新途径，从而为有效实现肿瘤早期检测、早期治疗、延长患者生存期和提高生存质量展示了良好的应用前景。