MR影像示踪的中性粒细胞药物输运体系靶向治疗术后脑胶质瘤

The highly infiltrative nature of glioma cells and the existence of blood brain barrier in the brain are the main reasons for high recurrence rate after surgery and low therapeutic efficiency of chemotherapy drugs. The inflammation reaction occurs in the brain after surgical resection. Neutrophils, a type of polymorphonuclear leukocyte, play a critical role in immune responses. Based on the innate tropism of neutrophil towards inflammation, a novel drug delivery system by utilizing neutrophil as carriers to mediate therapeutic nanoparticles is an attractive approach for treating post-surgical glioma. Theranostic cells can be achieved by integrating magnetic mesoporous silica nanoparticles (MMSNs) with neutrophils. The in vitro and in vivo models will be applied to evaluate theranostic cells’ ability to cross blood brain barrier, realize T2-weighted MR imaging-guided glioma-specific drug delivery and therapeutic monitoring. This project is expected to establish a novel cell-based bioactive material for crossing blood brain barrier and delivering therapeutic agents to glioma, and promote the development of cell-based biomaterials in drug delivery and treatment of disease.

脑胶质瘤浸润型的生长方式和脑组织内血脑屏障的存在是导致脑胶质瘤术后易复发、化疗药物治疗效率低的重要原因。手术可引发脑组织内一系列的炎症反应，而中性粒细胞作为机体内主要的免疫细胞，在炎症反应的发生、发展过程中起到重要作用。由此本项目提出将中性粒细胞作为药物输运的载体应用于术后脑胶质瘤治疗的研究思路。拟将具有T2-MR成像和载药能力的磁性介孔氧化硅纳米颗粒（MMSNs）与炎症趋向性的中性粒细胞结合，制备靶向术后脑胶质瘤的细胞诊疗剂，在细胞水平上研究其生物学效应及对炎症因子的趋向能力；建立体内术后脑胶质瘤模型，评价细胞示踪、体内分布、T2-MR影像引导下颅内药物递送及疗效监测。本项目的成功实施将建立一种基于细胞载体用于跨越血脑屏障和靶向脑胶质瘤的药物递送系统，有望推动细胞基生物活性材料在药物输运及疾病治疗上的应用。

脑胶质瘤起源于神经胶质细胞，是最常见的中枢神经系统恶性肿瘤。在颅内呈浸润性生长，与周围脑组织无清楚边界，因此手术难以彻底切除，导致术后极易复发。此外，由于颅内血脑屏障的存在，限制了大部分药物进入肿瘤组织，导致脑胶质瘤放疗化疗不敏感。本项目利用免疫系统中重要的中性粒细胞，作为穿越血脑屏障的靶向细胞载体，同时结合载药的磁性介孔氧化硅纳米颗粒，得到具有磁共振成像性能的细胞诊疗剂（ND-MMSNs）。当通过静脉注射到达术后脑胶质瘤炎性区域后，高度激活的载药中性粒细胞可形成中性粒细胞胞外诱捕网，同时释放载药纳米颗粒并进入到浸润的肿瘤细胞，达到磁共振影像示踪“特洛伊木马”细胞抑制脑肿瘤复发的目的。研究结果表明，ND-MMSNs在体内外具有较强的炎症趋向性，较好地抑制肿瘤生长和复发的效果，并显著延长术后荷瘤小鼠的生存期。此项目的开展对细胞基生物活性材料等新型医药载体的研究起到了积极的推动作用。