Ansari Md Meraj, Ahmad Anas, Mishra Rakesh Kumar, Raza Syed Shadab, Khan Rehan
Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India.
Laboratory for Stem Cell and Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College Hospital, Sarfarazganj, Lucknow 226003, India.
ACS Biomater Sci Eng. 2019 Jul 8;5(7):3380-3397. doi: 10.1021/acsbiomaterials.9b00427. Epub 2019 Jun 12.
Rheumatoid arthritis (RA) is the most prevalent autoimmune disease affecting about 1% world population. Zinc (Zn) is necessary for the maintenance of bone homeostasis and the level of Zn was reported to be decreased in RA patients and collagen-induced arthritic rats. Effective delivery of Zn has been reported using zinc gluconate but oral absorption of Zn from zinc gluconate (ZG) is very low in humans. Zn supplementation reduces disease severity in patients suffering from chronic, refractory RA and exerts mild and transient side effects. The aim of this study was to synthesize and characterize zinc gluconate-loaded chitosan nanoparticles (ZG-Chit NPs) and to evaluate and compare therapeutic efficacy of ZG-Chit NPs and zinc gluconate against collagen-induced RA in Wistar rats. The nanoparticles were formulated by ionic gelation method and the hydrodynamic diameter was 106.5 ± 79.55 nm as measured using DLS. The particle size, shape, and surface morphology was further confirmed by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. These nanoparticles showed good cytocompatibility against foreskin fibroblasts (BJ) and L929 cells. Arthritic rats were treated with ZG (20 mg/kg body weight, intraperitoneally) and equivalent doses of ZG-Chit NPs. The treatment of both ZG and ZG-Chit NPs reduced the severity of arthritis as evidenced by reduced joint swelling, erythema, and edema but ZG-Chit NPs exhibited superior efficacy. Furthermore, it was found that ZG and ZG-Chit NPs attenuate biomarkers of inflammation (C-reactive protein, myeloperoxidase, nitric oxide, TNF-α, and IL-1β) and oxidative stress (articular elastase, lipid peroxidation, catalase, glutathione, and superoxide dismutase). The results of the histopathology further confirmed that ZG-Chit NPs markedly suppressed infiltration of inflammatory cells as compared to ZG at the ankle joint tissue. Immunohistochemical analysis also revealed that treatment with ZG-Chit NPs resulted in reduced pro-inflammatory marker (TNF-α, IL-6, and iNOS) expression and enhanced SOD1 expression. Overall, this study suggests that ZG and ZG-Chit NPs suppressed the severity of arthritis plausibly mediated by attenuation of inflammation and oxidative stress and more importantly ZG-Chit NPs exhibited superior efficacy as compared to ZG.
类风湿关节炎（RA）是最常见的自身免疫性疾病，影响着全球约1%的人口。锌（Zn）对于维持骨骼稳态至关重要，据报道，RA患者和胶原诱导的关节炎大鼠体内的锌水平会降低。已有报道使用葡萄糖酸锌有效递送锌，但人体对葡萄糖酸锌（ZG）中锌的口服吸收非常低。补充锌可减轻慢性难治性RA患者的疾病严重程度，并产生轻微且短暂的副作用。本研究的目的是合成并表征负载葡萄糖酸锌的壳聚糖纳米颗粒（ZG-Chit NPs），并评估和比较ZG-Chit NPs与葡萄糖酸锌对Wistar大鼠胶原诱导的RA的治疗效果。通过离子凝胶法制备纳米颗粒，使用动态光散射（DLS）测量其流体动力学直径为106.5±79.55nm。通过透射电子显微镜、扫描电子显微镜和原子力显微镜进一步确认了颗粒大小、形状和表面形态。这些纳米颗粒对包皮成纤维细胞（BJ）和L929细胞显示出良好的细胞相容性。用ZG（20mg/kg体重，腹腔注射）和等效剂量的ZG-Chit NPs治疗关节炎大鼠。ZG和ZG-Chit NPs的治疗均减轻了关节炎的严重程度，表现为关节肿胀、红斑和水肿减轻，但ZG-Chit NPs显示出更高的疗效。此外，发现ZG和ZG-Chit NPs可减轻炎症生物标志物（C反应蛋白、髓过氧化物酶、一氧化氮、TNF-α和IL-1β）和氧化应激（关节弹性蛋白酶、脂质过氧化、过氧化氢酶、谷胱甘肽和超氧化物歧化酶）。组织病理学结果进一步证实，与ZG相比，ZG-Chit NPs在踝关节组织中显著抑制了炎症细胞浸润。免疫组织化学分析还显示，用ZG-Chit NPs治疗可降低促炎标志物（TNF-α、IL-6和诱导型一氧化氮合酶）的表达，并增强超氧化物歧化酶1（SOD1）的表达。总体而言，本研究表明，ZG和ZG-Chit NPs可能通过减轻炎症和氧化应激来抑制关节炎的严重程度，更重要的是，与ZG相比，ZG-Chit NPs表现出更高的疗效。
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