蛋白和核酸门控的新型介孔氧化硅输送体系的构筑及其控制释放性能

Controlled release of targeted drug delivery systems is to improve therapeutic efficacy and reduce amounts of drugs and their side effects. Zero premature release and stimuli-responsive controlled release of pharmaceutical cargos are two very important prerequisites that impact the therapeutic efficacy and cytotoxicity of drug delivery. Biocompatible mesoporous silica, with unique pore structure and ease of surface functionalization, is considered to be promising nanocarriers and ideal scaffolds for stimuli-responsive targeted drug delivery systems. Controlled release of biomacromolecule-gated mesoporous silica drug delivery systems has attracted much attention recently. Taking the advantage of the multivalent interactions between ligands and protein receptors in a variety of biological processes and the intercalative binding of drug molecules with double-stranded DNA, the project is to construct novel protein- (lectin and histidine-rich protein) and nucleic acid-gated mesoporous silica delivery systems in combination of nanotechnology, self-assembly, biomolecular recognition, and controlled release. Surface densities and spatial distribution of carbohydrate, and iminodiacetic acid, and DNA intercalator-functionalized mesoporous silica by self-assembly are regulated elaborately to enhance biomacromolecule binding affinity. Stimuli-responsive controlled release of the delivery systems driven by pH reduction, competitive binding of biomolecules, and reduction of disulfide bonds connected with intercalators can be realized under the physiological conditions. The delivery systems have promising applications for biosensors and in vivo site-specific drug release.

药物靶向输送和控制释放是提高给药疗效、减少药物用量及其毒副作用的关键。影响给药疗效和细胞毒性的两个最重要条件是药物零提前释放及刺激响应控制释放。生物相容性介孔氧化硅具有的独特孔道结构和易表面功能化性质，被认为是智能控释给药最有前途的药物纳米容器和理想的载体材料。生物大分子门控的介孔氧化硅药物输送系统及其控制释放引起人们的极大关注。基于许多生物过程中配体与蛋白受体的多重相互作用以及药物分子与双链DNA嵌插结合作用模式，集纳米技术、自组装技术、生物识别和控制释放于一体，本项目提出构筑蛋白（凝集素蛋白和富含组氨酸蛋白）和核酸门控的新型介孔氧化硅控释体系，调控介孔氧化硅表面自组装甘露糖和亚胺二乙酸功能配体以及DNA嵌插基团的表面密度和空间分布，增强生物大分子结合亲和性。通过降低pH和生物分子竞争结合以及还原连接嵌插基团的二硫键，实现生理条件的刺激响应控制释放。推动介孔氧化硅药物输送系统的生物应用。

刺激响应介孔氧化硅（MSN）纳米载药体系能够有效提高药物的治疗效果和降低药物的毒副作用。构筑了伴刀豆球蛋白门控的甘露糖功能化的MSN纳米载药体系，研究了pH响应和高浓度葡萄糖竞争结合的药物控制释放性能。构筑了金属配位与金属配位肌红蛋白协同门控的乙二胺三乙酸功能化的MSN纳米载药体系，研究了pH响应的药物控制释放性能。构筑了天然DNA门控的二硫键连接的吖啶胺功能化的MSN纳米载药体系，研究了二硫键还原、DNA热至变性和核酸酶水解三重刺激响应的药物控制释放以及结合两种刺激的逻辑门控制释放性能。构筑了天然DNA门控的Ti(IV)配位膦酸功能化的嵌入金纳米棒的MSN纳米双载药体系，研究了核酸酶和近红外光响应的两种药物的同时控制释放以及结合两种刺激的两种药物的连续控制释放性能。构筑了环糊精门控的双重动态共价键（硼酸酯和二硫键）连接的苯硼酸和脂肪胺功能化的MSN纳米双载药体系，研究了pH响应的两种药物的同时控制释放以及结合两种刺激的两种药物的连续控制释放性能。分别构筑了羧基化柱芳烃阀控的苯并咪唑阳离子和联吡啶阳离子功能化的MSN纳米载药体系，研究pH、金属配位和竞争结合的三重刺激响应的药物控制释放性能。构筑了羧基化柱芳烃与二硫键连接的苯并咪唑阳离子两亲分子共组装形成的超分子囊泡载药体系，研究了二硫键还原、pH、CO2、金属配位和生物胺竞争结合的五重刺激响应的药物控制释放性能。构筑了ZnO量子点门控的二硫键连接的空心MSN纳米载药体系，研究了pH和二硫键还原响应的药物控制释放性能。构筑了ZnO量子点门控的介孔碳纳米载药体系，研究了pH响应的药物控制释放性能。构筑了具有多重作用结合位点和生物相容性印迹空穴的蛋白印迹自组装单层膜。发展了一种甘露糖功能化的核壳纳米粒子通过磁富集分离实现伴刀豆球蛋白和葡萄糖的SERS串联检测方法。构筑的这些多功能纳米载药体系在肿瘤治疗方面具有潜在的应用前景。