特殊形貌氧化硅纳米颗粒的制备、修饰及其在基因载体中的应用

Silica nanomaterials are potential nonviral gene carrier with high transfection efficiency due to their unique properties. The design for tailored morphologies, sizes and surface modification of mesoporous silica nanoparticles may provide new properties and performances since they are the main factors governing the cellular uptake and the process of cellular delivery. Herein, we try to investigate the relationship between morphologies, sizes and surface modifications of silica nanoparticles and the performances of the hybrid gene carrier. Inorganic-Organic hybrid gene carrier will be developed employing cationic polymer functionalized silica nanoparticles via atom transfer radical polymerization (ATRP). First, silica nanoparticles with controlled sizes and morphologies will be synthesized. Then the initiator for ATRP reaction will be introduced to the surface of silica nanoparticles. After that, PDMAEMA chains with low molecular weight could be attached to silica nanoparticles via ATRP. The PDMAEMA chains could be further polymerized with PEG blocks with hydroxyl groups via ATRP and the hydroxyl groups of the carrier can be further modified for the attachment of targeting molecules for tumor tissue. Finally, the new type of silica hybrid nanoparticle gene carrier with high efficiency, low toxicity and targeting function will be fabricated and screened. This project will promote the combination of material sciences with biomedicine and open new avenues for the fabrication of gene delivery systems with high performances. Moreover, the gene carriers obtained using this strategy may be of practical significance and will find promising application in gene therapy.

氧化硅纳米材料因其独特的性质有望用于构建高性能非病毒基因载体，新颖形貌及表面修饰的设计可能赋予载体特殊的性能。本项目力图研究氧化硅纳米颗粒的形貌、尺寸及表面修饰等因素对基因载体性能的影响。拟结合ATRP手段，制备以氧化硅纳米颗粒为核、阳离子聚合物功能化的有机无机复合载体。首先设计合成多种形貌及尺寸的氧化硅纳米颗粒，然后在纳米颗粒上引入ATRP引发剂官能团, 通过ATRP法制备低分子量PDMAEMA聚合物刷，构建特殊形貌的氧化硅基纳米基因载体；为增进载体的屏蔽效应，PDMAEMA链可进一步通过ATRP法引入带有羟基官能团的PEG嵌段；而后利用载体的羟基官能团固定能与肿瘤特异性靶点相结合的靶向物，以提高基因载体的靶向性，最终构建并筛选出具有靶向性、高效而低毒的新型氧化硅复合纳米基因载体。本研究将推动材料科学与生物医学的有机结合，加速高性能基因控释载体的研发。

基因治疗对癌症等重大疾病的治疗将会发挥巨大的作用，而其关键在于寻求一种理想的基因载体。氧化硅纳米颗粒因其独特的性质有望用于构建高效低毒的基因载体，本项目从基因载体的形貌、尺寸、结构和表面性质等方面入手，通过对材料的设计构建以氧化硅纳米颗粒为核、阳离子聚合物功能化的新型氧化硅纳米复合基因载体。首先发展了一种“Grafting from”的方法，利用ATRP反应将低分子量的PDMAEMA聚合物刷接枝到氧化硅纳米颗粒上制备基因载体，然后研究了不同尺寸和形貌的基因载体对基因转染性能的影响。结果表明，一维、尖角以及空心的纳米结构有利于性能提高。在此基础上，设计合成了具有六个对称尖角结构的空心星形氧化硅纳米载体，对其进行阳离子聚合物PGEA修饰，利用其内部空腔载药，外表面络合基因，并且引入二硫键，实现药物和基因在肿瘤部位的响应性释放。此外，也利用含二硫键的前体制备了包含抗癌药物的可降解氧化硅复合纳米基因载体，材料在肿瘤部位的降解促进了药物和基因的释放，并且有利于载体的清除，实现了pH和GSH双响应的药物/基因联合治疗，取得了很好的体内治疗效果。这些低毒高效基因载体的构建对提高基因治疗的理论水平和实际应用都有很大的推动作用，也为癌症治疗提供了新的途径。