可靶、可控、可视复合纳米制剂的设计及介导肝癌综合治疗的机制研究

Hepatocelluar carcinoma seriously threatens human's health in the word, especially in our country. Improving outcome of the treatment depends on synthetic therapy since the current strategy has not always been suf?ciently effective. Nanocomposites with multifunction of drug delivery, diagnosis, therapy and monitoring treatment represent a promising opportunities for cancer synthetic therapy. Based on our previous study in which ZnO nanoparticles with anticancer drug mediated the combination modalites of chemotherapy and photodynamic therapy to induce the remarkable inhibition of hepatocarcinoma cells, we will fabricate the Fe3O4/ZnO nanocomposites loaded doxorubicin (DOX) and modified transferring receptor monoclonal antibody to explore the new strategy of synthetic therapy for hepatocelluar carcinoma. The nanocompisites could improve tumor targeting performance because of the integration of passive targeting, active targeting and magnetic targeting, and DOX could be intelligently released in the weak acid tumor site and tumor cells due to the pH-responsive structure DOX-ZnO. The relative in vitro anticancer activity and the mechanism of the nanocompisites mediated chemotherapy of DOX, hyperthermia of Fe3O4, and photodynamic therapy of ZnO as well as the different combinations of the single modality against hepatocarcinoma cells will be investigated in this study. We will further study the biocompatibility and body distribution of the nanocompisites in the animal model of liver cancer, and monitor the outcome of the synthetic therapy mediated by the nanocompisites with visual magnetic resonance in vivo, which would provides evidence for the clinic.

肝癌严重威胁人类健康，尤我国为高发国之一，治疗效果尚不理想，提高疗效依赖于综合治疗。纳米复合物具有药物传输、诊断、治疗及疗效监测等多项功能，因此在肿瘤综合治疗领域具有广阔的应用前景。基于我们前期研究结果：纳米ZnO携载化疗药物联合化疗、光动力学治疗高效抑制肝癌细胞，丰富内涵、扩展外延，本项目将构建新型Fe3O4/ZnO纳米复合物装载阿霉素（DOX）及偶联转铁蛋白受体单克隆抗体的多功能制剂，探索肝癌综合治疗新策略。即有机结合纳米粒子被动靶向、抗体主动靶向及磁导靶向提高肿瘤靶向效能，进而利用制剂中DOX-ZnO载药方式呈现的pH 敏感性释药特性，实现在微酸性的肿瘤组织和细胞中智能选择性控释；体外研究制剂对肝癌细胞的DOX化疗、Fe3O4热疗、ZnO光动力学治疗及不同治疗方式组合的综合疗效和机制；应用肝癌动物模型，进行安全性、体内分布及磁共振可视化监测综合治疗疗效及机制研究，为临床应用提供依据。

肝癌严重威胁人类健康，尤我国为高发国之一，治疗效果尚不理想，提高疗效依赖于综合治疗。纳米复合物具有药物传输、诊断、治疗及疗效监测等多项功能，因此在肿瘤综合治疗领域具有广阔的应用前景。本项目构建新型Fe3O4/ZnO纳米复合物装载阿霉素（DOX）及偶联转铁蛋白受体单克隆抗体的多功能制剂，探索肝癌综合治疗新策略。该纳米制剂有机结合被动靶向、主动靶向及磁导靶向提高药物传输系统靶向性能，进而利用制剂中DOX-ZnO 载药方式呈现的pH 敏感性释药特性，实现在微酸性的肿瘤组织和细胞中智能控释药物。体内外研究结果表明，在外加磁场力的作用下，Fe3O4@ZnO/Dox磁靶向传输药物至肝癌肿瘤组织、细胞，提高化疗疗效。此外，在紫外激发下，Fe3O4@ZnO显示良好的光敏剂特性，即光动力学治疗再次打击肿瘤细胞，诱导肿瘤细胞凋亡，即光动力学治疗、化疗联合协同作用，导致更为有效的抗肿瘤效应。在项目研究中我们惊喜地发现，半导体材料紫外线激发产生的光化学反应，同样可以被X线（X-ray）激发诱导，换句话说，ZnO也可以基于X线能量转换产生活性氧（ROS），而X线具有较强的组织穿透能力，可以作用于深部肿瘤。因此，在项目中我们继续探索Fe3O4@ZnO作为放疗增敏剂的能力。我们基于Fe3O4@ZnO纳米复合物装载Dox 及偶联TfR Ab，成功构建了Fe3O4@ZnO/Dox/TfR Ab肝癌诊疗一体化制剂：靶向药物传输、同步放化疗、可视化磁共振成像。Fe3O4@ZnO/Dox/TfR Ab的主动靶向作用可致肝癌SMMC-7721细胞化疗药物含量明显增多，提高化疗疗效。我们创新性地发现Fe3O4@ZnO在短程、低剂量X线下可起到放疗增敏作用，进而同步放化疗抗肿瘤，阻滞肿瘤细胞于G2/M期，抑制肿瘤细胞增殖。而且在项目研究中我们注意到Fe3O4@ZnO纳米复合物中的Fe3O4组分是一种优良的磁共振造影剂。无创、可视化的磁共振成像体内疗效监测研究表明，Fe3O4@ZnO/Dox/TfR Ab介导的同步放化疗可明显抑制原位肝癌模型肿瘤的生长。总之，基于Fe3O4/ZnO设计的可靶、可控、可视复合纳米制剂开辟了肝癌诊疗的新途径，为临床应用提供了依据。