多级响应性空心碳酸钙纳米复合物的可控制备及在肿瘤联合治疗中的应用

To realize highly effective and safe cancer treatment, researchers with medical or other backgrounds have devoted a large amount of effort in the past decades. Recently, with the fast advance of nanotechnology, it was found to be of great promise to improve the cancer treatment efficacy by utilizing the tumor microenvironment (TME) responsive nano-drug carriers, which are not only efficient in enhancing the tumor accumulation and intratumoral diffusion of those loaded drugs, but be able to reasonably combine several different cancer therapeutics together. In this project, based on our previous experience on the fabrication of TME responsive nanotheranostics, our goal is to develop a number of biodegradable hollow calcium carbonate (CaCO3) nanocomposites with multi-staged TME responsiveness as well as excellent chemotherapeutic and Fenton oxidation capacity for potential cancer combination therapy. With biocompatible and pH responsive CaCO3 nanoparticles as the template, we could elaborately combine different TME responsive functional modules together by utilizing the strong coordination interaction between the organic ligands (e.g. gallic acid, GA) and metallic centers (e.g. cisplatin prodrug, Fe2+). Furthermore, we would carefully optimize their TME responsive size evolution profile and its impact on their corresponding tumor accumulation, deep tissue penetration, chemotherapeutic & Fenton oxidation capacity, and their biodegradability by adjusting the types of those organic ligands, metallic centers as well as their feeding ratios. By completing the projects in this proposal, we try to figure out innovative strategy for the fabrication of TME responsive nano-drug carriers, which are promising for highly effective and safe cancer treatment.

安全高效的肿瘤治疗一直以来是医学等众多学科试图攻克的难题。随着纳米技术的快速发展，近期的研究表明，肿瘤微环境响应性纳米药物载体能够有机整合多种治疗手段、提高药物在肿瘤内的富集与分布，进而实现安全高效的肿瘤治疗。在本项目中，申请人拟在前期工作的基础上，以具备良好生物相容性、pH响应性和生物可降解性的纳米碳酸钙为模板，利用有机配体（没食子酸）与金属节点（顺铂前药、Fe2+）之间的配位作用，将具有不同响应性的功能基元有机整合起来，构建一系列对肿瘤微环境具有多级响应性、兼具化疗和芬顿氧化能力的空心碳酸钙纳米复合物。申请人将通过调节有机配体与金属节点的种类及二者的比例等因素，实现对材料的肿瘤微环境响应性尺寸变化、肿瘤富集与深组织渗透、化疗与芬顿氧化以及体内降解代谢等性质的优化，进而实现安全高效的肿瘤联合治疗。我们力争通过本项目的开展，为发展新型响应性纳米药物载体与肿瘤联合治疗策略提供新的理论支撑。

肿瘤微环境是导致当前众多肿瘤治疗失败的关键因素之一。肿瘤微环境中微酸、乏氧、高活性以及免疫抑制等生理指标会导致瘤内药物扩散受阻、癌细胞耐药、免疫逃逸，进而促进肿瘤复发与转移。针对这一问题，申请人通过本项目研究发展了一种表面保护刻蚀策略用于制备空心碳酸钙纳米复合物，利用碳酸钙的微酸响应性分解性质实现了药物在瘤内的高效富集与扩散，并发现利用材料的芬顿催化能力来放大细胞内的氧化应激水平可以损伤线粒体并减少ATP的合成，进而通过阻止药物外排的方式来逆转肿瘤的多耐药性，实现对耐药肿瘤的高效治疗。在此基础上，利用声敏剂包裹的空心碳酸钙作为钙离子载体可以造成细胞内钙离子超载并放大胞内氧化应激水平，进而显著提高肿瘤声动力治疗的疗效；同时，通过构建长效的Fe2+载体作为芬顿催化剂，可以通过放大细胞内的氧化应激水平来提高化疗、放疗等传统肿瘤治疗手段的疗效。另外，通过构建碳酸钙基蛋白药物载体实现了肿瘤微酸响应性蛋白递送，同时发现利用脂肪氧化酶能够将肿瘤残渣原位转化为脂质自由基并诱导残余肿瘤细胞发生铁凋亡，高效抑制残余肿瘤生长的同时还能激活机体抗肿瘤免疫反应已协同增强射频免疫联合治疗的疗效。进一步研究发现，利用碳酸钙的质子中和能力能够有效中和肿瘤微酸环境，并通过联合IDO1抑制剂能够协同逆转肿瘤免疫抑制性，显著提高肿瘤放化疗的疗效并通过诱导机体产生特异性的抗肿瘤免疫反应来抑制肿瘤转移并预防肿瘤复发。通过本项目研究，发现利用碳酸钙基纳米载体能够实现肿瘤微酸响应性分子/离子的高效递送与瘤内扩散，揭示了肿瘤内氧化应激放大、微酸中和与肿瘤治疗增效的协同机制。.项目执行期间，在Nature Communications、Chem、Advanced Materials、Coordination Chemistry Reviews等国内学术期刊发表第一/通讯作者论文19篇；申请国家发明专利9件，授权3件；申请获批了国自然面上项目一项；两次入选美国科睿唯安公布的“全球高被引科学家名单”（Highly Cited Researchers, 2019和2021年）；培养博士和硕士毕业生各1名。