pH/NIR双重智能响应系统靶向联合治疗类风湿关节炎的研究

As the final effector cells of rheumatoid arthritis (RA), synovial cells are the most important factors leading to joint dysfunction. However, the therapy of RA mainly depends on the immunosuppression and inhibition of inflammation factors. While seldom therapy focuses on the hyperplasia of synovial cells. Here, we fabricate magnetic nanoparticles with excellent photoyhermal effect to targeted delivery infliximab (INF), a chimeric monoclonal antibody against tumour necrosis factor alpha (TNF-α), and methotrexate (MTX) to synovial cells. Nonetheless, many difficulties shall be overcome during the process of drug delivery, including "PEG Dilemma" and "Charge Contradiction". PEG-SH, which will fall off with the trigger of NIR light, is used to modify the Fe3O4 nanoparticles. Hemoglobin (HGB) is also adopted onto the magnetic nanoparticles so as to construct charge-reversal delivery system. After intravenous injection, the multifunctional nanoparticles can accumulated in the inflammatory joints with the help of external magnetic field. By the local NIR light irradiation in the joints, multifunctional nanoparticles display strong photothermal effect which induces the triggered-removal of PEG and the release of INF. In the acidic condition of the inflammatory joints, HGB realizes the transition from negative charge to positive charge, which will promote the uptake of the nanoparticles. With the combination of simultaneous INF, MTX and PTT, the inflammation factors will be inhibited and the hyperplastic cells will be killed with significantly increased possibility. The combined therapy mediated by our dual-sensitive magnetic nanoparticles provide not only new method for the treatment of RA, but also new ideas for PTT applications.

滑膜细胞为类风湿关节炎（RA）的最终效应细胞，其活化后具有增生和入侵性，可以破坏软骨及骨组织，是导致骨关节功能障碍最直接的因素。然而，目前RA的治疗主要集中于炎症因子抑制与免疫抑制，针对滑膜增生的治疗很少。鉴于此，本研究拟构建负载抗TNF-α药物英夫利西单抗和细胞毒药物甲氨蝶呤并具有强光热效应的磁性纳米粒；同时，针对纳米粒在传递过程中存在的“PEG困境”和“电荷矛盾”的问题，利用具有光控脱除功能的PEG-SH及“电荷反转”功能的血红蛋白进行修饰，实现药物向滑膜细胞的高效递送及光热-化疗同步治疗。通过关节局部近红外光照射，控制PEG的脱除与英夫利西单抗的释放；同时，在关节微酸性环境下，血红蛋白实现由负电到正电的转变，促进纳米粒子的高效摄取。英夫利西单抗、甲氨蝶呤与光热三者协同作用，在炎症因子抑制的同时，彻底杀伤增生细胞。本项目不仅为RA的治疗做了有益的尝试，也为光热治疗的应用提供新的思路。

成纤维样滑膜细胞（FLSs）作为类风湿关节炎（RA）的最终效应细胞，其活化后具有增生和入侵性，可以破坏软骨及骨组织，是导致关节功能障碍最直接的因素。目前RA的治疗主要集中于炎症因子抑制与免疫抑制，针对FLSs增生的治疗相对较少，而且相关治疗药物毒副作用较大。为了提高治疗效率，我们拟通过炎症因子抑制剂英夫利昔单抗（INF）及化疗药物甲氨蝶呤（MTX）协同作用，彻底抑制FLSs增生。为进一步降低药物全身性毒性，我们构建以Fe3O4纳米粒为基础的药物载体，利用其光热效应实现药物的定位释放，而光热治疗同时将与化疗产生协同抗RA效果。.在靶向纳米载体设计中，面临“尺寸效应”、“PEG困境”等问题，我们首先通过实验优化了靶向RA组织的最佳Fe3O4纳米粒尺寸，并考察RA光热治疗（PTT）的可行性。在此基础上，负载INF、MTX，构建MTX-Fe3O4-S-PEG-INF纳米载体，该载体在NIR激光下实现HS-PEG-INF的胞外智能脱落，有助于纳米粒的细胞摄取。同时，Fe3O4的pH敏感性将促进MTX在酸性环境下释放。在PTT的配合下，达到抑制炎症因子和杀伤增生细胞的目的。本项目不仅为RA的治疗做了有益的尝试，也为光热治疗的应用提供了新的思路。