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Injectable Click-Crosslinked Hyaluronic Acid Depot To Prolong Therapeutic Activity in Articular Joints Affected by Rheumatoid Arthritis.
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2019-07-02 , DOI: 10.1021/acsami.9b04979
Jiyoung Seo , Seung Hun Park , Min Ju Kim , Hyeon Jin Ju , Xiang Yun Yin , Byoung Hyun Min , Moon Suk Kim

The aim of this study was to design a click-crosslinked hyaluronic acid (HA) (Cx-HA) depot via a click crosslinking reaction between tetrazine-modified HA and trans-cyclooctene-modified HA for direct intra-articular injection into joints affected by rheumatoid arthritis (RA). The Cx-HA depot had significantly more hydrogel-like features and a longer in vivo residence time than the HA depot. Methotrexate (MTX)-loaded Cx-HA (MTX-Cx-HA)-easily prepared as an injectable formulation-quickly formed an MTX-Cx-HA depot that persisted at the injection site for an extended period. In vivo MTX biodistribution in MTX-Cx-HA depots showed that a high concentration of MTX persisted at the intra-articular injection site for an extended period, with little distribution of MTX to normal tissues. In contrast, direct intra-articular injection of MTX alone or MTX-HA resulted in rapid clearance from the injection site. After intra-articular injection of MTX-Cx-HA into rats with RA, we noted the most significant RA reversal, measured by an articular index score, increased cartilage thickness, extensive generation of chondrocytes and glycosaminoglycan deposits, extensive new bone formation in the RA region, and suppression of tumor necrosis factor-α or interleukin-6 expression. Therefore, MTX-Cx-HA injected intra-articularly persists at the joint site in therapeutic MTX concentrations for an extended period, thus increasing the duration of RA treatment, resulting in an improved relief of RA.

中文翻译:

可注射的点击交联透明质酸库可延长受类风湿关节炎影响的关节的治疗活性。

本研究的目的是通过四嗪修饰的 HA 和反式环辛烯修饰的 HA 之间的点击交联反应设计点击交联的透明质酸 (HA) (Cx-HA) 储库,用于直接关节内注射到受关节损伤影响的关节中。类风湿性关节炎(RA)。与 HA 长效制剂相比,Cx-HA 长效制剂具有明显更多的水凝胶样特征和更长的体内停留时间。甲氨蝶呤 (MTX) 负载的 Cx-HA (MTX-Cx-HA) 可轻松制备为可注射制剂,可快速形成 MTX-Cx-HA 储库,并在注射部位持续较长时间。MTX-Cx-HA 储库中的 MTX 体内生物分布表明,高浓度的 MTX 在关节内注射部位持续较长时间,而很少分布到正常组织。相比之下,直接关节内注射单独的 MTX 或 MTX-HA 可导致注射部位快速清除。将 MTX-Cx-HA 关节内注射到 RA 大鼠后,我们注意到最显着的 RA 逆转,通过关节指数评分、软骨厚度增加、软骨细胞和糖胺聚糖沉积的广泛生成、RA 中广泛的新骨形成来衡量区域,并抑制肿瘤坏死因子-α 或白介素-6 的表达。因此,关节内注射的 MTX-Cx-HA 在关节部位持续保持治疗 MTX 浓度较长一段时间,从而增加 RA 治疗的持续时间,从而改善 RA 的缓解。通过关节指数评分、软骨厚度增加、软骨细胞和糖胺聚糖沉积的广泛生成、RA区域广泛的新骨形成以及肿瘤坏死因子-α或白介素-6表达的抑制来测量。因此,关节内注射的 MTX-Cx-HA 在关节部位持续保持治疗 MTX 浓度较长一段时间,从而增加 RA 治疗的持续时间,从而改善 RA 的缓解。通过关节指数评分、软骨厚度增加、软骨细胞和糖胺聚糖沉积的广泛生成、RA区域广泛的新骨形成以及肿瘤坏死因子-α或白介素-6表达的抑制来测量。因此,关节内注射的 MTX-Cx-HA 在关节部位持续保持治疗 MTX 浓度较长一段时间,从而增加 RA 治疗的持续时间,从而改善 RA 的缓解。
更新日期:2019-07-02
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