双相同轴打印支架靶向阻断巨噬细胞SIRPα和CSF-1R通路调控肿瘤免疫抑制微环境的研究

3D打印骨修复体具有可定制外形、适合治疗分子功能化装载，有潜力用于骨肿瘤术后肿瘤复发抑制与个性化组织修复。肿瘤免疫抑制微环境基于CSF-1R通路诱导巨噬细胞表型变化是骨肿瘤复发的关键因素。申请人前期将CSF-1R抑制剂装载于3D打印钙磷基支架可调控巨噬细胞表型并减缓肿瘤生长，却未能完全抑制。研究发现，抑制剂的递送与释放方式，以及SIRPɑ通路介导的巨噬细胞吞噬抑制是影响其效用的主要原因。因此，本课题以苯硼酸修饰的聚酰胺胺树形分子为SIRPα抗体和CSF-1R抑制剂的载体构建巨噬细胞靶向递药颗粒；研发载递药颗粒复合水凝胶为缓释外相，钙磷基体系为成骨内相同轴打印构建核壳结构治疗支架。考察支架结构和对治疗分子释放等理化性能；对巨噬细胞表型和吞噬，对破骨细胞活化和成骨分化的调控作用和机理。体内考察免疫调控对肿瘤抑制的作用机制。通过课题研究，有望为骨肿瘤治疗提供新方法和新思路。

3D printed bone repair implants have customizable shapes and are suitable for functional loading of therapeutic molecules, which show promising potential to be used for tumor recurrence suppression and personalized tissue repair after bone tumor surgery. The changes of macrophage phenotype induced by tumor immunosuppressive microenvironment based on CSF-1R pathway is a key factor in bone tumor recurrence. Previously, the applicant regulated local macrophage phenotypes and slowed tumor growth with CSF-1R inhibitor loaded 3D printed calcium phosphate scaffolds, but failed to completely inhibit. It was found that the way the inhibitor is delivered and released, as well as SIRP pathway-mediated macrophage phagocytosis inhibition, are the major factors affecting its efficacy. Therefore, in this study, a macrophage-targeting drug delivery system would be constructed by using phenylboric acid-modified polyamide amine dendritic molecule as the carrier of SIRPα-blocking antibody and CSF-1R inhibitor. A composite hydrogel sustained releasing the drug delivery system would be developed as the external phase, and coaxial print with calcium phosphate-based system as the osteogenic internal phase to construct an immunoregulation therapeutic scaffold with core-shell structure. The structure and physicochemical properties of the scaffold, such as release behavior of therapeutic molecules, would be investigated. Regulating effects of the scaffold on phenotype change and phagocytic behavior of macrophages, activation of osteoclasts and osteogenic differentiation of stem cells, and related mechanisms would be carefully studied in vitro. Mechanisms of tumor inhibition effects of the immunoregulation scaffold would be further investigated in vivo. Through this research, it is expected to provide new ideas and methods for the treatment of bone tumors.