多模态影像引导相变介孔硅仿生系统靶向递送MTX治疗类风湿关节炎

Rheumatoid arthritis (RA), characterized by multi-joint affection, is an autoimmune disease with high probability of disability. We have conducted serious experiments of drug delivery system of RA in an effort to reduce the side effect of methotrexate (MTX) - the initial treatment of RA. However, the liposomes we made have considerable disadvantages of low encapsulation ratio, drug leakage and weak of stability. The inflammatory joints of RA patients pathologically accumulate a large number of inflammatory cells, particularly macrophages that migrated from peripheral blood. Hollow mesoporous silica nanoparticles (HMSNs) is hollow silica spheres with numerous hole on their shells, which have serious advantages - great ability of drug loading, splendid stability, big specific surface area, good biocompatibility, etc. Additionally, perfluoropentane (PFP) is a type of perfluorocarbon (PFC) with great stability. Ultrasound sonication can vaporize PFP via acoustic droplet vaporization (ADV) forming ultrasound image in both B-mode and contrast enhanced mode. Therefore, we have designed MTX-loaded Phase-change Hollow Mesoporous Silica Nanoparticles (MTX-PFP-HMSNs) phagocytosed by macrophages to build up a biomimetic delivery system. When macrophages, dyed with DiR, will have migrated to the inflammatory joints, we’ll kill them by ADV to release MTX. Because of DiR cytomembrane near-infrared dye, we will achieve that multi-image (fluorescence image, photoacoustic image and ultrasound image) guided drug delivery treatment of RA.

类风湿性关节炎(RA)是一种侵犯多关节的高致残性自身免疫病，甲氨喋呤(MTX)为一线用药，为克服其长期全身应用毒副作用大的问题，本课题组前期开展了载MTX脂质体靶向治疗RA的研究，但其存在载药量较低、递送过程漏药、稳定性欠佳等不足。病理学显示，RA患者发病关节中有大量炎症细胞聚集，其中的巨噬细胞是由外周血不断迁移过来的，具有靶向趋化作用。中空介孔硅(HMSNs)是一种中空介孔的二氧化硅纳米球，具有载药力强、稳定性高、比表面积大等优势；全氟戊烷(PFP)稳定性较高，超声激发能使其发生液气相变，并具有超声造影功能。本项目拟用DiR标记的巨噬细胞吞噬负载MTX-PFP的HMSNs，建立相变介孔硅仿生系统，发挥免疫逃逸作用，高效递送MTX至关节炎部位，并应用超声介导相变杀死巨噬细胞，达到MTX定点控释治疗RA的作用，实现荧光/光声/超声多模态成像引导下可视化靶向治疗RA的目的。

类风湿关节炎（RA）是一种侵犯多关节的高致残性自身免疫病，甲氨喋呤(MTX)为一线用药，但易致肝肾功能损害、骨髓抑制等，因此如何提高MTX疗效减少其全身毒副作用为RA治疗的关键。本项目原设计用巨噬细胞吞噬同时负载MTX与全氟戊烷（PFP）的中空介孔硅（HMONs），构建载药相变介孔硅仿生体系用于RA靶向治疗。然而因HMONs负载MTX效果欠佳，故用阿霉素（DOX）替代MTX并将该系统充分应用于三阴性乳腺癌的治疗，获得良好的抑瘤效果。此外，本课题组以骨髓间充质干细胞（BMSCs）吞噬生物泡（GVs）构建了生物泡-干细胞复合体，并将其联合MTX用于RA靶向治疗。该体系不仅实现了BMSCs的体内超声实时示踪，还实现了BMSCs的成骨分化，提高了MTX的疗效。本项目同时开发了载药相变介孔硅仿生系统和生物泡-干细胞复合体，并将其分别应用于抗肿瘤领域和抗类风湿关节炎领域，为细胞药物靶向递送系统开创了新的研究思路，且为干细胞疗法的体内超声实时示踪提供了无创性新方法。