pH或氧化还原响应性生物大分子基胶囊的组装及肿瘤诊疗研究

针对肿瘤组织与正常组织的生理差异性，利用层层组装技术，可控制备肿瘤微环境响应的生物大分子基胶囊，实现肿瘤的高灵敏诊断和高效联合治疗。主要研究内容包括通过软模板辅助下的溶胶-凝胶法和沉淀法制备多孔二氧化硅纳米粒子和碳酸钙颗粒，利用吸附或转相结晶负载化疗或光动力抗癌药物分子。基于硼酸酯键、席夫碱键、二硫键或二硒键等pH或氧化还原响应的动态共价键作用，进一步在其表面层层组装修饰或未修饰的多糖或蛋白等生物大分子以及近红外区域的无机或有机光热转换纳米颗粒，外接聚乙二醇，修饰肿瘤细胞识别分子，建立兼具诊断功能的长循环、肿瘤靶向性、可控药物释放和联合高效杀伤肿瘤的药物递送体系。重点研究胶囊的稳定性、生物相容性和血液循环耐受性，详细阐明胶囊结构-性质-功能之间的相互关系，并综合离体和活体实验，系统评估其诊断水平和疗效，探索其在临床上应用的可行性。通过该项目的实施，有望开发出新的高端肿瘤诊疗一体化制剂。

According to the general differences of tumors and normal tissues, by the layer-by-layer technique, biomacromolecule-based capsules responding to tumor microenvironment will be assembled in a controlled manner for cancer diagnose with high sensitivity and therapy with high efficiency simultaneously. Porous silicon and calcium carbonate nanoparticles will be prepared by sol-gel and precipitation under the assistance of soft templates, respectively. Then, anticaner chemical or photodynamic drugs will be uploaded into these carries above by absorption or phase transfer. Furthermore, using polysaccharides or proteins and organic or inorganic photo-thermal-conversion nanostructures under near infrared irradiation(such as gold nanorods, gold nanocages and polyaniline microcages) as building blocks, driven by pH or redox-responsive dynamic chemical bonds (such boric acid ester, Schiff's bases, disulfide or diselenide bonds), modified with polyethylene glycol (PEG) and recognizing molecules,long cycled and targeted delivery systems which can release drugs controllably and kill tumor cells powerfully will be constructed. Stability, biocompatibility and endurance of capsules mentioned above will be investigated and their relationships of structures, properties and effects will be demonstrated in detail. By the relative experiment in vitro and in vivo, diagnose ability and therapy effect will be estimated systematically for clinical applications. Novel advanced theranostic agents will be developed during carrying out this project.