Deng Ya-Si, Shen Xin-Yang, Long Meng-Ting, Zheng Hao, Li Bin, Wang Wei, Yu Huang-He
Traditional Chinese Medicine and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine Changsha 410208, China.
Zhongguo Zhong Yao Za Zhi. 2024 Jun;49(11):2906-2919. doi: 10.19540/j.cnki.cjcmm.20240304.303.
Rheumatoid arthritis(RA) is a condition in which the joints are in a weakly acidic environment. In RA, RA fibroblastlike synoviocytes( RAFLS) in the joints become abnormally activated and secrete a large amount of matrix metalloproteinases(MMPs), and the receptor protein CD44 on the cell membrane is specifically upregulated. Xuetongsu(XTS), an active ingredient in the Tujia ethnomedicine Xuetong, is known to inhibit the proliferation of RAFLS. However, its development and utilization have been limited due to poor targeting ability. A biomimetic XTS-Prussian blue nanoparticles(PB NPs) drug delivery system called THMPX NPs which can target CD44 was constructed in this study. The surface of THMPX NPs was modified with hyaluronic acid(HA) and a long chain of triglycerol monostearate(TGMS) and 3-aminobenzeneboronic acid(PBA)(PBA-TGMS). The overexpressed MMPs and H+ in inflammatory RAFLS can synergistically cleave the PBA-TGMS on the surface of the nanoparticles, exposing HA to interact with CD44. This allows THMPX NPs to accumulate highly in RAFLS, and upon near-infrared light irradiation, generate heat and release XTS, thereby inhibiting the proliferation and migration of RAFLS. Characterization revealed that THMPX NPs were uniform cubes with a diameter of(190. 3±4. 7) nm and an average potential of(-15. 3± 2. 3) m V. Upon near-infrared light irradiation for 5 min, the temperature of THMPX NPs reached 41. 5 ℃, indicating MMPs and H+-triggered drug release. Safety assessments showed that THMPX NPs had a hemolysis rate of less than 4% and exhibited no cytotoxicity against normal RAW264. 7 and human fibroblast-like synoviocytes(HFLS). In vitro uptake experiments demonstrated the significant targeting ability of THMPX NPs to RAFLS. Free radical scavenging experiments revealed excellent free radical clearance capacity of THMPX NPs, capable of removing reactive oxygen species in RAFLS. Cell counting kit-8 and scratch assays demonstrated that THMPX NPs significantly suppressed the viability and migratory ability of RAFLS. This study provides insights into the development of innovative nanoscale targeted drugs from traditional ethnic medicines for RA treatment.
类风湿性关节炎（RA）是一种关节处于弱酸性环境的病症。在RA中，关节中的RA成纤维样滑膜细胞（RAFLS）异常活化并分泌大量基质金属蛋白酶（MMPs），且细胞膜上的受体蛋白CD44特异性上调。血通素（XTS）是土家族民族药血通中的一种活性成分，已知其可抑制RAFLS的增殖。然而，由于靶向能力差，其开发利用受到限制。本研究构建了一种名为THMPX NPs的可靶向CD44的仿生XTS-普鲁士蓝纳米颗粒（PB NPs）药物递送系统。THMPX NPs的表面用透明质酸（HA）、硬脂酸甘油单酯长链（TGMS）和3-氨基苯硼酸（PBA）（PBA-TGMS）进行了修饰。炎症性RAFLS中过表达的MMPs和H+可协同切割纳米颗粒表面的PBA-TGMS，使HA暴露出来与CD44相互作用。这使得THMPX NPs在RAFLS中高度蓄积，在近红外光照射下，产生热量并释放XTS，从而抑制RAFLS的增殖和迁移。表征显示THMPX NPs为均匀的立方体，直径为（190.3±4.7）nm，平均电位为（-15.3±2.3）mV。近红外光照射5分钟后，THMPX NPs的温度达到41.5℃，表明MMPs和H+触发了药物释放。安全性评估表明，THMPX NPs的溶血率小于4%，对正常RAW264.7和人成纤维样滑膜细胞（HFLS）无细胞毒性。体外摄取实验证明了THMPX NPs对RAFLS具有显著的靶向能力。自由基清除实验表明THMPX NPs具有出色的自由基清除能力，能够清除RAFLS中的活性氧。细胞计数试剂盒-8和划痕实验表明，THMPX NPs显著抑制了RAFLS的活力和迁移能力。本研究为从传统民族药开发用于治疗RA的创新纳米级靶向药物提供了思路。
