硅质体纳米药物载体的应用基础研究

Nowadays, the severe challenge for treatment of cancers is how to eradicate premalignant and early-stage cancer, identify the right size and location of the tumor, targetedly deliver drugs to cancers, and overcome the barrier of drug resistance. Liposomes have received increasing attention as possible carriers for diagnostic or therapeutic agents. However, the insufficient stability of liposomes may limit their applications. Attacking this problem head on, we developed nanohybrid liposomal cerasomes. Like traditional liposomes, cerasomes show good biocompatibility and biodegradability, but much higher stability than liposomes. This proposal will develop new multifunctional ceresomes to co-deliver several kinds of drugs with different anticancer mechanisms to reduce the drug resistance by chemotherapy combined with gene therapy or chemotherapy combined with immunotherapy. Superparamagnetic iron oxide (SPIO) nanoparticles have been widely used as magnetic resonance imaging (MRI) contrast agent. Furthermore, cerasomes are used to load both anticancer drugs and SPIO, followed by conjugation of targeting molecules (folic acid, HER2 etc.) onto the surface of cerasomes. Thus, we can investigate various applications of nanotheranostic cerasomes in noninvasive visualization of drug distribution, drug release kinetics, drug accumulation at target sites, drug therapeutic effect, and disease diagnosis. By administration of such multifunctional cerasomes, MRI can be applied to identify the size and location of the tumor, and then, under real-time MRI guidance and monitoring, tumor therapy could be targetedly carried out based on the diagnostic imaging results, avoiding the damage of normal tissues. Finally, after the treatment procedure, the effectiveness of the therapy could be evaluated by MRI-assisted diagnosis to determine whether or not to carry out further treatment. This may resolve the problems relating to low specificity of anticancer drugs and multidrug resistance.

如何在最初期侦测癌症、准确指出癌症位置、向癌细胞准确投递药物以及克服适应性耐药是现有的癌症治疗方法面临的严峻挑战。脂质体是当前医药领域中最热门的纳米药物载体，但稳定性差的缺点限制了它的推广应用。为了解决这一难题，课题组研制了硅质体。它与脂质体一样，生物相容性好，可生物降解，不会残留体内，但稳定性比脂质体显著提高。本项目拟在已有的基础上进一步构建多功能硅质体，共输送多种不同作用机制的药物，通过化疗药物、基因药物与免疫治疗药物联用，以期降低癌细胞的耐药性。进而，以硅质体同时负载抗癌药物和磁共振造影剂，并用特异性配体进行靶向修饰，联合超灵敏靶向显像、靶向治疗及应答检测等多种功能，探索在体评价药物与靶点结合效率及药物在靶部位释放的成像方法，研究硅质体药物的作用机制和降低癌细胞耐药性的机理，最终达到分子成像监控下的癌症治疗目的，可望有效解决抗癌药物靶向性低和癌细胞适应性耐药的问题。

脂质体是当前医药领域中最热门的纳米药物载体，但稳定性差的缺点限制了它的推广应用。为了解决这一难题，本项目通过分子设计合成了一系列含有二氧化硅前体的复合脂质，并以此为原料通过溶胶-凝胶法和自组装方式制得具有脂质双层膜的复合脂质体，即硅质体。硅质体通过Si-O-Si键把构成囊泡的脂质分子连接起来，维持了脂质体的特征，但稳定性却比传统脂质体显著提高。它既结合了二氧化硅纳米粒子和脂质体的优点，又克服了各自的缺点；既具有很高的稳定性，又具有很好的生物相容性。它不仅可包埋各种水溶性和脂溶性药物，而且可包埋两亲性药物，并可通过其表面的硅羟基将单克隆抗体、叶酸等靶向分子连接到硅质体上，从而实现靶向给药。因此，硅质体是一种理想的药物载体。.研制了可对超声和微波敏感的硅质体。在超声或微波照射下，硅质体可快速释放其装载的药物，使肿瘤部位瞬间达到很高的药物浓度，显著提高了对肿瘤细胞的杀伤力，可望解决癌细胞适应性耐药的问题。研制了光敏剂载药量高达33%以上的卟啉硅质体，实现了荧光/磁共振双模态成像引导的精准光动力治疗和化疗的联合治疗。制备了复合脂质体纳米盘，并利用穿膜肽分别对其侧边和平面进行修饰。研究发现，侧边修饰比平面修饰的摄取率提高17倍，而且纳米盘在肿瘤部位的蓄积强于球形硅质体。侧边修饰的纳米盘提高了肿瘤荧光成像效果，可实现高灵敏检测。设计合成了两亲性氟尿苷-喜树碱共轭化合物，并以此为成膜材料制备了含有脂质双层膜结构的纳米胶囊，载药量高达60%以上。.合成10种脂质化合物，研制了12种硅质体纳米药物载体。发表SCI论文58篇，包括3篇高被引论文，其中影响因子大于10的7篇。主编专著1部(上下2卷，Springer出版)。申请发明专利23项。获省自然科学一等奖1项（排名第一）。培养博士毕业生12名，在读博士生9名，2人获教育部学术新人奖。培养硕士毕业生8名，在读硕士生3名。在国内外学术会议上作邀请报告20次以上。组织召开第554次香山科学会议和2017国际分子影像与微创治疗会议。