Abstract
BackgroundCelastrol 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.MethodsThe 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.ResultsCSL@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.ConclusionHollow 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.
Highlights
Osteoarthritis (OA) is a prevalent joint disease worldwide characterized by the progressive destruction of articular cartilage, joint inflammation, osteophytes, subchondral bone remodeling, joint effusion and pain [1]
The data of the Hollow mesoporous silica nanoparticles (HMSNs) and HMSNs-Cs group showed no significant difference with the OA condition. All these results demonstrated the pH-responsive property of CSL@HMSNs-CS and that cell viability could be reversed by treatment with CSL and CSL@HMSNsCS
The results of the present study indicated that CSL@ HMSNs-Cs provide an ideal treatment by downregulating the expression of Matrix metalloproteinases (MMPs)-3 and MMP-13, which could be responsible for the anti-inflammatory effect previously mentioned
Summary
Osteoarthritis (OA) is a prevalent joint disease worldwide characterized by the progressive destruction of articular cartilage, joint inflammation, osteophytes, subchondral bone remodeling, joint effusion and pain [1]. The mechanisms of OA pain are complex and involve abnormalities of both the peripheral and central nervous systems [5]. The pathogenesis of OA involves disruption of the delicate balance between repair and destruction of joint tissues due to mechanical stress and inflammatory cytokines [7]. Efforts in targeted toward knee osteoarthritis (KOA) therapeutic strategies have largely focused on systemic drug interventions, the mainstay of which is the long-term use of nonsteroidal anti-inflammatory drugs [8]. Systemic drug interventions have been reported to be related to a high incidence of cardiovascular events and gastrointestinal side effects [9]. Arthroscopic knee surgery has little to no effect on pain relief, and the benefits are limited in time accompanied by adverse events such as deep venous thrombosis [10]. 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
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