聚氨酯支架联合甘露糖修饰的GQA聚氨酯胶束搭载阿霉素和Fe3O4局部埋植对术后胶质母细胞瘤的综合诊疗作用及机制研究

In situ recurrence of GBM after surgery is a major problem. Due to the obstruction of BBB and BBTB and the formation of postoperative glial scar, the adjuvant treatment is unsatisfactory. For this reason, the 3D waterborne biodegradable polyurethane porous scaffold is proposed as an implantable carrier to deliver doxorubicin/Fe3O4 encapsulated mannose-GQA-polyurethane micelles locally in the tumor cavity after GBM surgery. The implantable drug delivery system (DDS) is supposed to get rid of BBB and carry drugs and MRI contrast agents to the residual GBM by inducing macrophages as vehicles, which will reduce systemic side effects of these drugs. We will first construct and characterize the scaffold-micelle composite DDS in vitro, including drug release characteristics, safety and the effect of GBM inhibition. At the same time, the mouse orthotopic GBM model was established, and the scaffold-micelle drug-loading system was embeded after GBM resection to verify the theranostic effects and to explore the mechanism in vivo. The novel idea of ​​combining the biological scaffold and polymer micelles as a local composite drug delivery model enables multimodal therapy of post-operation of GBM and makes it possible to monitor tumor recurrence. This will solve the problem of repeated recurrence, re-operation, and ineffective radiotherapy and chemotherapy in patients with GBM, which is of great significance.

胶质母细胞瘤（GBM）手术治疗后原位复发是一大难题，且由于血脑屏障（BBB）和血脑肿瘤屏障（BBTB）的阻碍及术后胶质瘢痕的形成，辅助治疗不理想。为此本项目提出以3D水性生物可降解的聚氨酯多孔支架为可植入载体，搭载甘露糖修饰的GQA聚氨酯胶束包裹阿霉素/Fe3O4，在GBM手术后埋植于瘤腔，利用巨噬细胞输送药物和MRI显影剂到残余肿瘤病灶，避开BBB并降低全身的毒副作用。我们首先构建并表征支架-胶束复合载药体系，在体外验证载药体系的药物释放特性、安全性及抑制GBM的作用。同时建立小鼠原位GBM模型，通过术后埋植载药体系，论证诊治效果并探讨体内作用机制。将生物支架和聚合物胶束结合的局部复合输送药物模式这一新颖想法，可实现GBM术后的多模态可视化治疗并使得监测肿瘤复发成为可能，一举多得。有效解决了GBM患者术后反复复发、再次手术、且放化疗无效的难题，具有重要的意义。

胶质母细胞瘤（GBM）手术治疗后原位复发是一大难题，且由于血脑屏障（BBB）和血脑肿瘤屏障（BBTB）的阻碍及术后胶质瘢痕的形成，辅助治疗不理想。本课题旨在以3D水性生物可降解的PU多孔支架为载体，搭载具有环境响应性的药物及造影剂，在GBM手术后埋植于瘤腔，实现药物和MRI造影剂的局部输送，避开BBB并降低全身的毒副作用。同时，由于PU支架和胶束靶向GAMMs的特性以及GAMMs参与GBM侵袭浸润的特性，可绕过胶质瘢痕靶向输送到GBM与正常脑组织的边界，进行定点精准释放杀灭浸润肿瘤细胞，这为GBM手术常不能全切导致残余肿瘤快速复发的难题提供了治疗的新思路。经过反复探索制备方法，优化调整技术路线，成功研发出3D水性生物可降解的PU多孔支架与氧化还原响应性PTX-PDCs前药胶束的复合载药体系，以支架为胶束载体，实现了常用化疗药物的局部可控输送；同时，新型PU支架复合载药体系可高效共载并输送化疗药物前药和Fe3O4纳米粒至GBM内部及周边GAMMs，绕过BBB，成功实现了对残余GBM的精准可视化杀伤，有效预防了GBM的术后复发。本项目的成果有望解决GBM患者术后反复复发、再次手术、且放化疗无效的难题，具有重要的意义。