两亲杯芳烃自组装生物医用纳米材料

The core of nanomedicine is nanomaterials, and the development of new nanomaterials is an important source of innovation to promote the continuous development of nanomedicine. Macrocyclic amphiphiles are suitably modified from macrocyclic receptors, deemed as cyclic oligomers of traditional amphiphiles, which display benign assembly performance comparing with polymersomes. Moreover, the most intriguing superiority is the host-guest recognition sites at the surfaces of their self-assemblies. Consequently, by integrating their recognition and assembly properties, developing self-assembled nanomaterials based on macrocyclic amphiphiles would pave a new avenue for nanomedicine. In this project, we focus on “self-assembled biomedical nanomaterials based on calixarene amphiphiles”. First, we propose to synthesize novel amphiphilic calixarene derivatives; Second, we explore their molecular recognition and self-assembly properties; Finally, in virtue of integrating classical polymer materials, we would develop one new kind of smart nanocarrier materials for antitumor drugs, which demonstrates several advantages, including multiple targeting, theranostics, combined chemotherapy and photodynamic therapy, and anti-multidrug resistance. Through the implementation of this project, we will strive to achieve source innovation in calixarene-based biomedical materials, providing new methods and developing new materials for antitumor nanomedicine.

纳米医学的核心基础是纳米材料，发展新型纳米材料是推动纳米医学不断发展的重要创新源泉。大环两亲由大环受体分子适当修饰而成，可视为传统两亲分子的环状寡聚物，展现出优良的组装特性，可与聚合物两亲组装相媲美。此外，大环两亲组装体的最大特点在于其表面特定主客体识别位点。因此，综合其识别与组装特性，发展大环两亲自组装纳米材料并深入开发其生物医药功能将为纳米医学带来新的发展契机。本项目中我们将集中开展“两亲杯芳烃自组装生物医用纳米材料”研究工作。首先是功能导向的新型两亲杯芳烃的设计合成，进而挖掘其分子识别与组装等理化性质，最终通过与经典高分子材料的融合，发展出一类新型的智能抗肿瘤纳米药物载体材料，兼具多重靶向性、诊疗一体化、化疗/光动力组合治疗和抗多药耐药性等特性。通过本项目的实施，力争在基于杯芳烃的生物医用材料方面取得源头创新，为抗肿瘤纳米药物提供新方法，发展新材料。

新型生物医用材料的研发是推动医疗精准化发展的重要手段，与生命健康这一国家重大需求密切相关。随着超分子化学的蓬勃发展及与生物医药领域的不断交叉融合，超分子大环主体日益成为重要的生物医用材料基元。而大环两亲作为具有特定识别位点的新型两亲分子，近年来受到了广泛的关注。本项目选用具有优良骨架预组织结构和独特空腔识别性质，并且制备简单、易于衍生化的杯芳烃作为核心骨架，围绕“两亲杯芳烃生物医药材料”集中开展。设计合成了23种功能导向的新型杯芳烃衍生物，并系统考察了杯芳烃的识别和组装等理化性质。在此基础上，开发了一系列新型智能抗肿瘤药物载体材料。同时，团队还拓展了两亲杯芳烃的其他生物医药功能。重要进展包括：(1) 系统研究了两亲杯芳烃的组装行为，指出了杯芳烃组装体交换动力学慢、组成均一、堆积致密等特点，为杯芳烃组装体的发展提供了新的生长点。(2) 针对肿瘤微环境的特点，发展了ATP、精胺、乏氧等刺激响应的载药材料，实现了对肿瘤的选择性成像和靶向治疗。(3) 发展了多重刺激响应的载药材料，进一步提高了药物释放精准度。(4) 发展了可用于肿瘤组合治疗的载药材料，实现了对组合药物的比率递送。(5) 探索了两亲杯芳烃组装体的其他生物医药功能，包括抑制蛋白纤维化和解毒毒性大分子等。本项目综合利用杯芳烃的识别与组装性质，构建了系列充分体现杯芳烃价值和特色的超分子新体系，并开发了多种生物医药功能，为肿瘤等重大疾病的防治提供了新的策略和材料。同时，对推动超分子体系向功能化发展具有重要科学意义。依托本项目的支持，团队共发表论文28篇，其中包括Nat. Chem. (1篇)，Nat. Commun. (1篇)，Adv. Mater. (3篇)，Angew. Chem. Int. Ed. (4篇)，Chem. Soc. Rev. (1篇) 等，申请国家发明专利4项，均已授权。