Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, Shanxi University of Chinese Medicine, Jinzhong, People's Republic of China.
Xi'an International Medical Center Hospital, Xi'an, People's Republic of China.
Int J Nanomedicine. 2024 Apr 6;19:3259-3273. doi: 10.2147/IJN.S457004. eCollection 2024.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease involving synovial inflammation and joint destruction. Although therapeutic drugs for RA have some efficacy, they usually cause severe side effects and are expensive. RA is characterized by synovial hyperplasia, intra-articular hypoxia, upregulated expression of matrix metalloproteinases, and excessive accumulation of reactive oxygen species. The adverse microenvironment further aggravates activated macrophage infiltration. Therefore, controlling the microenvironment of diseased tissues and targeting the activated macrophages have become new therapeutic targets in RA patients.
Here, microenvironment-targeting micelles (PVGLIG-MTX-Que-Ms) were synthesized using the thin film hydration method. In the inflammatory microenvironment, PVGLIG was cleaved by the highly expressed MMP-2, PEG was eliminated, MTX was exposed, macrophage activation was targeted, and Que enrichment was enhanced. The cytotoxicity, targeting, antioxidant, and anti-inflammatory properties of drug-loaded micelles were tested in vitro. The drug-loaded micelles were used to treat CIA rats. In vivo targeting, expression of serum inflammatory factors, immunohistochemistry of the articular cartilage, and changes in immunofluorescence staining were observed.
The developed micelles had a particle size of (89.62 ±1.33) nm and a zeta potential of (-4.9 ±0.53) mV. The IC value of PVGLIG-MTX-Que-Ms (185.90 ±6.98) μmol/L was significantly lower than that of free Que (141.10 ±6.39) μmol/L. The synthesized micelles exhibited slow-release properties, low cytotoxicity, strong targeting abilities, and significant anti-inflammatory effects in vitro. In vivo, the drug-loaded micelles accumulated at the joint site for a long time. PVGLIG-MTX-Que-Ms significantly reduced joint swelling, improved bone destruction, and decreased the expression of serum inflammatory factors in CIA rats.
The smart-targeting micelles PVGLIG-MTX-Que-Ms with strong targeting, anti-inflammatory, cartilage-protective, and other multiple positive effects are a promising new tool for RA treatment.
类风湿关节炎（RA）是一种慢性系统性自身免疫性疾病，涉及滑膜炎症和关节破坏。尽管 RA 的治疗药物具有一定的疗效，但它们通常会引起严重的副作用且价格昂贵。RA 的特征是滑膜增生、关节内缺氧、基质金属蛋白酶表达上调以及活性氧物质的过度积累。不良的微环境进一步加剧了活化巨噬细胞的浸润。因此，控制病变组织的微环境并针对活化的巨噬细胞已成为 RA 患者的新治疗靶点。
采用薄膜水化法合成了靶向微环境的胶束（PVGLIG-MTX-Que-Ms）。在炎症微环境中，PVGLIG 被高表达的 MMP-2 切割，PEG 被消除，MTX 暴露，靶向巨噬细胞激活，Que 富集增强。体外测试了载药胶束的细胞毒性、靶向性、抗氧化和抗炎特性。用载药胶束治疗 CIA 大鼠。观察体内靶向性、血清炎症因子表达、关节软骨免疫组化及免疫荧光染色变化。
所研制的胶束粒径为（89.62±1.33）nm，zeta 电位为（-4.9±0.53）mV。PVGLIG-MTX-Que-Ms 的 IC 值（185.90±6.98）μmol/L 明显低于游离 Que（141.10±6.39）μmol/L。合成的胶束具有缓慢释放特性，体外具有低细胞毒性、强靶向性和显著的抗炎作用。体内，载药胶束在关节部位长时间聚集。PVGLIG-MTX-Que-Ms 显著减轻 CIA 大鼠的关节肿胀，改善骨破坏，降低血清炎症因子的表达。
具有强靶向性、抗炎、软骨保护等多种积极作用的智能靶向胶束 PVGLIG-MTX-Que-Ms 是一种很有前途的 RA 治疗新工具。
