自组装杂化纳米凝胶体系及其用于肿瘤微环境响应性诊疗的研究

Supramolecular hydrogel formed by self-assembly in water through noncovalent interactions have already been shown great potential in the field of biomedicine because of their unique advantages, such as good biocompatibility, readily functional modification and inherent biodegradability. In this project, based on the human’s own immune system and the structure-function features of upramolecular nanogels, we would like to design and prepare a kind of tumor microenvironment-responsive supramolecular nanogels system to simulate human immune response mechanism for deep tumor visual therapy. We design to regulate the hydrophobicity of substrates around the interface of magnetic iron oxide/solution to trigger the self-assembly of peptide hydrogelators, and then the hydrogel nanoshell will be successfully fabricated surrounding the surface of nanoparticles. After controlling the reaction conditions, the core-shell supramolecular nanogels will be collected. Subsequently, the supramolecular nanogels can be served as the nanocarrier to physically immobilize the bienzyme lactic acid oxidase (LOD) and myeloperoxidase (MPO) which exhibit great responsiveness to lesion environment (rich in lactate and H2O2). The deep tumor therapy performance of this responsive nanogel system through enzymatic controlling singlet oxygen will be further investigated by evaluating the tumor damage casued by the responsive production of singlet oxygen. Meanwhile, this magnetic nanogels can also be served as contrast agents for highly efficient T2-weighted MR imaging. This project will provide a new attempt for exploring and developing a safe, efficient and non-invasive tumor diagnose and treatment method.

通过非共价键自组装形成的超分子水凝胶由于具有良好的生物相容性，易于功能化和固有的生物降解性等优点，在生物医学领域有着很大的应用前景。本项目从安全高效的肿瘤微环境响应性治疗的应用出发，结合人体自身免疫机制和超分子水凝胶的结构-功能特性，设计制备一类具有肿瘤微环境响应性的超分子杂化纳米凝胶体系，模拟人体免疫反应机制，实现肿瘤区磁共振成像和响应性酶动力学治疗。设计采用磁性四氧化三铁为功能模板，界面调控成胶底物的亲疏水性诱导其进行界面组装，控制反应条件得到核壳结构超分子纳米凝胶，并对病变部位（富乳酸和H2O2）环境具有响应性的双酶分子乳酸氧化酶（LOD）和髓过氧化物酶（MPO）进行负载，得到超分子纳米凝胶复合酶诊疗剂材料，通过考察LOD/MPO酶联体系响应微环境刺激产生单线态氧对肿瘤组织的损伤，研究利用酶控单线态氧进行肿瘤治疗和磁共振成像的性能表现，为肿瘤微环境响应性诊断和治疗的发展提供新的尝试。

本项目从安全高效的肿瘤微环境响应性诊疗出发，结合有机体生物氧化抗感染机制和水凝胶的结构-功能特性，以无机纳米材料为内核，发展温和的限域纳米界面诱导成胶方法，成功制备超分子或超分子-高分子复合纳米凝胶材料，同时担载串联酶组分，构建系列杂化纳米凝胶基诊疗剂体系，响应肿瘤微环境发生高效的生物催化反应，实现安全有效的肿瘤超声/光声成像诊断以及生物氧化治疗的研究，为更安全高效的肿瘤诊疗提供了新的尝试。取得的代表性成果主要包括：1）设计制备磁性氧化铁/级联酶杂化纳米凝胶诊疗剂材料，用于肿瘤微环境（富乳酸和H2O2）响应的超声成像及pH/超声响应性药物释放研究；2）发展物理-生物氧化协同治疗策略，通过光热/酶串联多级放大肿瘤区ROS，打破肿瘤细胞氧化还原稳态，用于安全高效的肿瘤治疗，同时结合超分子-高分子复合凝胶结构特点，实现增强超声/光声成像；3）仿生生命体基质酶结构及其生化防御机制，构建隔室化多酶纳米反应器，实现高效的级联酶生物催化，用于生物氧化治疗；4）引入导电高分子，发展温和高效的酶/导电高分子交联固定方法，构建高性能生物界面，用于疾病实时诊断。在本项目的资助下，现已第一/共一和通讯作者在国内外重要期刊Angewandte Chemie International Edition, ACS Applied Bio Materials, Sensors and Actuators B: Chemical等发表论文3篇。