Abstract:
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.
摘要:
类风湿性关节炎(RA)是关节处于弱酸性环境中的病症。在RA中,关节内的RA成纤维细胞样滑膜细胞(RAFLS)异常活化,分泌大量基质金属蛋白酶(MMPs),细胞膜上的受体蛋白CD44被特异性上调。雪通素(XTS),土家族民族药学通中的一种活性成分,已知抑制RAFLS的增殖。然而,由于靶向能力差,其开发和利用受到限制。本研究构建了一种仿生XTS-普鲁士蓝纳米颗粒(PBNP)药物递送系统,称为THMPXNP,可靶向CD44。THMPXNP的表面用透明质酸(HA)和长链三甘油单硬脂酸酯(TGMS)和3-氨基苯硼酸(PBA)(PBA-TGMS)修饰。炎症RAFLS中过表达的MMPs和H+可以协同切割纳米颗粒表面的PBA-TGMS,暴露HA与CD44相互作用。这允许THMPXNP在RAFLS中高度积累,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。表征表明THMPXNP是直径为(190。3±4。7)nm和平均电位为(-15。3±2.3)mV.近红外光照射5分钟,THMPXNPs的温度达到41。5℃,表明MMPs和H+触发的药物释放。安全性评估显示THMPXNP具有小于4%的溶血率并且不表现出对正常RAW264的细胞毒性。7和人成纤维细胞样滑膜细胞(HFLS)。体外摄取实验证明了THMPXNP对RAFLS的显著靶向能力。自由基清除实验揭示了THMPXNP优异的自由基清除能力,能够去除RAFLS中的活性氧。细胞计数试剂盒-8和划痕试验表明THMPXNP显著抑制RAFLS的活力和迁移能力。这项研究为从传统民族药物中开发用于RA治疗的创新纳米靶向药物提供了见解。