仿生制备活性矿物载体用于骨肉瘤术后免疫治疗和缺损修复

Surgical resection is the main strategy for clinical treatment of osteosarcoma. However, there are some problems brought along with the surgical process, including the difficulty to completely remove tumor cells and the bone defects. Therefore, the development of multifunctional biomaterials for intelligent drug release and promoting the regeneration of bone defects after the surgical treatment of osteosarcoma is significant in related research areas. In this project, considering the key problems in the clinical treatment of osteosarcoma and immunotherapy strategy, we will develop a biomimetic method to prepare a novel biomineral based carrier system, which can load and release PD-L1 antibody for immunotherapy of residual tumor cells and simultaneously promote the repair of bone defect. The biominerals will have bioactivity and high specific surface area, which are prepared by enzymes and phosphorus-containing biomolecules in a bionic microenvironment of native bone tissue. The as-prepared bioactive mineral carriers can efficiently loading / sustained release of PD-L1 antibody, and also can induce the osteogenic differentiation of stem cells. The key scientific problems and basic disciplines in the preparation process of biominerals based carrier system will be clarified. Then, we will evaluate the properties of immunotherapy and bone defect repair by using biomineral based carriers in the post-surgical osteosarcoma model, as well as the physical and biological properties of the biomineral based carriers. Through these efforts, we hope to develop and provide a scientific basis for a novel functional mineral carrier for osteosarcoma therapy.

手术切除是当前骨肉瘤临床治疗的主要方案，但存在肿瘤细胞难以完全清除和导致骨缺损的问题。发展可用于骨肉瘤术后智能化药物缓释和促进骨缺损再生的多功能生物材料将具有重要的研究意义。本项目针对当前骨肉瘤临床治疗中的关键问题并结合免疫治疗热点，创新地提出新型仿生策略，制备高生物安全性矿物载体系统，使其既可以pH响应地缓释PD-L1抗体免疫治疗术后残留肿瘤细胞，又可以发挥促进骨缺损修复的关键作用。具体上，拟仿生天然骨组织微环境，通过生物酶催化含磷生物分子水解，制备具有高比表面积的活性矿物载体，实现PD-L1抗体的高效装载/缓释和诱导干细胞成骨分化的生物活性；深入研究仿生制备活性载体策略中的关键科学问题，阐明仿生制备的基本规律；系统研究活性矿物载体的理化/生物学性质，及术后骨肉瘤模型的免疫治疗和骨缺损修复性能和作用机制。本项目的顺利实施将为骨肉瘤治疗用新型功能性活性矿物载体的制备和应用提供理论支持。

骨肿瘤及其引起的骨缺损治疗是骨科临床难题。手术切除、化疗及后续骨移植是其临床常用手段，但仍存在化疗效果不理想、易复发及材料生物活性低等问题。本项目创新性地发展了酶促仿生矿化、蛋白诱导仿生矿化等方法，获得了酶促合成无定型磷酸钙（EACP）生物矿物团簇、硒掺杂磷酸钙、Glut-5靶向的金属磷酸盐及具有缓释锰离子和免疫激活性能的复合载体系统等新型仿生材料。通过系统的体外和体内研究证实，所制备的多种材料体系具有通过逆转耐药性、激活先天和获得性免疫作用等方式治疗骨肉瘤，以及具有通过AMPK或自噬相关信号通路激活骨髓间充质干细胞分化，进而高效诱导骨缺损修复的综合性能。值得注意的是，本项目取得的部分研究成果，基于仿生矿化制备的磷酸钙纳米团簇在骨缺损修复上已经展现出了巨大的应用潜力，相关成果正在开展转化探索。以上研究成果为骨肉瘤、骨缺损的治疗和活性生物材料的创制提供了新的思路和研究基础，具有重要的科学意义和实际应用价值。上述研究成果已在国内外重要期刊上发表论文17篇，其中影响因子大于10的论文7篇；申请中国发明专利2项；培养博士、硕士研究生 4 名。综上，本项目已取得的成果已经达到和超过项目任务书规定的考核指标要求。