Celastrol has been proven effective in anti-inflammatory but was limited in the clinic due to the poor solubility and side effects induced by low bioavailability. Osteoarthritis has acidic and inflammatory environment. Our aim was to load celastrol into HMSNs and capped with chitosan to construct a pH-responsive nanoparticle medicine (CSL@HMSNs-Cs), which is of high solubility for osteoarthritis intra-articular injection treatment. The CSL@HMSNs-Cs were assembled and the characteristics were measured. The CSL@HMSNs-Cs was applied in vitro in the chondrocytes collected from rats cartilage tissue and in vivo in the MIA induced knee osteoarthritis rats via intra-articular injection. Cytotoxicity assay, pH-responsive release, pain behavior, MRI, safranin o fast green staining, ELISA and western blot analysis were applied to evaluate the bioavailability and therapeutic effect of CSL@HMSNs-Cs. CSL@HMSNs-Cs was stable due to the protection of the chitosan layers in alkaline environment (pH = 7.7) but revealed good solubility and therapeutic effect in acidic environment (pH = 6.0). The cytotoxicity assay showed no cytotoxicity at relatively low concentration (200 μg/mL) and the cell viability of chondrocytes stimulated by IL-1β was increased in CSL@HMSNs-Cs group. Paw withdrawal threshold in CSL@HMSNs-Cs group is increased, and MRI and Safranin O Fast Green staining showed improvements in articular surface erosion and joint effusion. The upregulated expression levels of IL-1β, TNF-α, IL-6, MMP-3 and MMP-13 and NF-κB signaling pathway of chondrocytes were inhibited in CSL@HMSNs-Cs group. Hollow mesoporous silica nanoparticles were an ideal carrier for natural drugs with poor solubility and were of high biocompatibility for intra-articular injection. These intra-articular injectable CSL@HMSNs-Cs with improved solubility, present a pH-responsive therapeutic strategy against osteoarthritis.

中文翻译：

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中空介孔二氧化硅纳米粒子在关节腔内递送Celastrol，用于针对膝盖骨关节炎的pH敏感型抗炎治疗。

已证明Celastrol具有抗炎作用，但由于溶解度低和生物利用度低而引起的副作用，在临床上受到限制。骨关节炎具有酸性和炎性环境。我们的目标是将Celastrol加载到HMSNs中，并用壳聚糖封端以构建对pH敏感的纳米药物（CSL @ HMSNs-Cs），该药物对骨关节炎关节内注射治疗具有高溶解性。组装了CSL @ HMSNs-C，并测量了特性。CSL @ HMSNs-Cs在体外应用于从​​大鼠软骨组织收集的软骨细胞中，并在体内通过关节内注射应用于MIA诱导的膝骨关节炎大鼠中。细胞毒性测定，pH响应释放，疼痛行为，MRI，番红蛋白或快速绿色染色，ELISA和western blot分析用于评估CSL @ HMSNs-Cs的生物利用度和治疗效果。CSL @ HMSNs-Cs由于在碱性环境（pH = 7.7）中对壳聚糖层的保护而稳定，但在酸性环境（pH = 6.0）中显示出良好的溶解性和治疗效果。CSL @ HMSNs-Cs组在相对较低的浓度（200μg/ mL）下没有细胞毒性，IL-1β刺激的软骨细胞的细胞活力增加。CSL @ HMSNs-Cs组的足爪退缩阈值增加，MRI和番红O型快速固绿染色显示关节表面糜烂和关节积液改善。CSL @ HMSNs-Cs组抑制了软骨细胞IL-1β，TNF-α，IL-6，MMP-3和MMP-13的表达水平以及NF-κB信号通路的表达。空心介孔二氧化硅纳米粒子是溶解性差的天然药物的理想载体，并且对于关节内注射具有高生物相容性。这些具有改善的溶解度的关节内注射的CSL @ HMSNs-Cs表现出针对骨关节炎的pH响应治疗策略。