“自杀式”生物催化纳米微反应器的构筑及其用于肿瘤的多模式治疗研究

Currently, it is one of the most promising new approaches to improve the efficiency of cancer treatment to selectively cut off the nutrient supply and metabolic pathways in tumor cells by means of biocatalysis regulation. In addition, intelligent biofunctional nanostructures based on the ordered assembly of active protein molecules and nanomaterials have been widely used in biomedical and other fields of intelligent biotechnology. This topic to explore the mediating function of with identification affinity peptide, within the tumor cells build a suicide biological nanotechnology catalytic reactor, with high specificity, high selectivity and diversification of enzyme catalytic reaction mechanisms such as the combination of synergies to achieve non-toxic medicine under the stimulus of the tumor microenvironment in situ before into therapeutic chemotherapy drugs, which will limotherapy and integrated into a platform to realize the tumor chemotherapy of multimodal treatment side effects and not normal tissues. In addition, the development of this new kind of therapeutic nanometer micro reactor can not only for the development of efficient enzyme/prodrug, transmission system and achieve accurate virus-free tumor therapy provide a new treatment strategies, but also through the activity of protein molecules and research on the laws of the assemble on the nanoparticles and the interaction law of digging, and cell for the theoretical basis for the design of multi-functional intelligent biological nanostructures.

当前，通过生物催化调控手段有选择地切断肿瘤细胞内营养供应和代谢途径实现“饥饿疗法”，是提高癌症治疗效率的一个最有希望的新途径。此外，活性蛋白分子与纳米材料的有序组装所构建的智能型生物功能纳米结构在生物医药和其它智能生物技术领域得到了广泛应用。本课题拟探索利用识别性亲和多肽的介导功能，在肿瘤细胞内构筑一种“自杀式”生物催化纳米微反应器，通过高特异性、高选择性和多元化的生物酶催化反应等机制的组合协同作用来实现无毒性前药在肿瘤微环境的刺激下原位转化为治疗性的化疗药物，进而将“饥饿疗法”与化疗整合到一个平台实现对肿瘤的多模式治疗而不对正常组织产生毒副作用。此外，开发这种新型的治疗性纳米微反应器不仅可以为发展高效的酶/前药传输体系和实现肿瘤无毒化精准治疗提供全新的治疗策略，还可通过对活性蛋白分子在纳米颗粒上亲和组装规律的研究以及与细胞相互作用规律的挖掘，为多功能智能型生物纳米结构的设计提供理论基础。

发展新型的肿瘤治疗手段，实现安全且高效的肿瘤无毒化精准治疗是当前众多学科的研究热点。本项目按照项目计划书实施，针对肿瘤细胞的异质性设计合成一种亲和肽介导的治疗性的纳米微反应器，并将“饥饿疗法”与化疗整合到一个平台实现了肿瘤的多模式靶向治疗。具体来说，首先借助借助合成生物技术手段实现了介孔硅亲和肽与肿瘤靶向性铁蛋白的融合表达，材料结合肽可作为“分子胶水”实现肿瘤识别性铁蛋白在纳米颗粒表面的定向有序组装。同时，探究了多肽的可控纤维化过程及其毒性作用，并借助具有病理微环境响应的多肽设计合成具有抗感染性能的多肽水凝胶。由此拓展了多肽在纳米颗粒表面定向组装、生物医用水凝胶设计与制备以及病理微环境响应性变构多肽的设计与应用研究。再者，选择可降解和无免疫原性的生物大分子组装在纳米颗粒表面构建了一系列具有肿瘤微环境响应性释放特性的纳米药物载体，这些载体可特异性响应肿瘤微环境变化实现药物的可控释放和无毒化精准治疗。这些智能型纳米药物载体不仅改善了难溶性药物的溶解度和生物利用度，同时赋予了药物递送的靶向性和缓控释性能，从而有效降低了药物的非特异性毒性作用。在此项目资助下，在Advanced Functional Material、Chemical Engineering Journal、Science China-Chemistry和Nanoscale Horizons等杂志发表论文10篇，申请国内发明专利2项，已授权1项。