Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China.
Department of Clinical pharmacy, The First Hospital of Jilin University, Changchun, China.
Drug Deliv. 2023 Dec;30(1):2173332. doi: 10.1080/10717544.2023.2173332.
Rheumatoid arthritis (RA), an autoimmune disease, is characterized by inflammatory cell infiltration that damages cartilage, disrupts bone, and impairs joint function. The therapeutic efficacy of RA treatments with the severely affected side remains unsatisfactory despite current treatment methods that primarily focus on anti-inflammatory activity, largely because of the complicatedly pathological mechanisms. A recently identified mechanism for RA development involves the interaction of RA autoantibodies with various proinflammatory cytokines to facilitate the formation of neutrophil extracellular traps (NETs), which increased inflammatory responses to express inflammatory cytokines and chemokines. Therefore, NETs architecture digestion may inhibit the positive-feedback inflammatory signal pathway and lessen joint damage in RA. In this work, deoxyribonuclease I (DNase) is connected to oxidized hyaluronic acid (OHA) via Schiff base reaction to extend the half-life of DNase. The modification does not influence the DNase activity for plasmid deoxyribonucleic acid hydrolysis and NETs' architecture disruption. Carboxymethyl chitosan is crosslinked with DNase-functionalised OHA (DHA) to form an injectable, degradable, and biocompatible hydrogel (DHY) to further strengthen the adhesive capability of DHA. Importantly, the collagen-induced arthritis model demonstrates that intra-articular injection of DHY can significantly reduce inflammatory cytokine expression and alleviate RA symptoms, which can be significantly improved by combining methotrexate. Here, a DNase-functionalised hydrogel has been developed for RA treatment by constantly degrading the novel drug target of NETs to decrease inflammatory response in RA.
类风湿关节炎（RA）是一种自身免疫性疾病，其特征是炎症细胞浸润，破坏软骨、破坏骨骼并损害关节功能。尽管目前的治疗方法主要侧重于抗炎活性，但严重影响侧的 RA 治疗疗效仍不尽人意，这主要是因为其病理机制复杂。最近发现的 RA 发展机制涉及 RA 自身抗体与各种促炎细胞因子的相互作用，以促进中性粒细胞胞外诱捕网（NETs）的形成，这增加了炎症反应，表达炎症细胞因子和趋化因子。因此，NETs 结构的消化可能会抑制正反馈炎症信号通路，并减轻 RA 中的关节损伤。在这项工作中，通过席夫碱反应将脱氧核糖核酸酶 I（DNase）与氧化透明质酸（OHA）连接起来，以延长 DNase 的半衰期。修饰不影响 DNase 对质粒脱氧核糖核酸水解和 NETs 结构破坏的活性。羧甲基壳聚糖与 DNase 功能化的 OHA（DHA）交联，形成可注射、可降解和生物相容的水凝胶（DHY），以进一步增强 DHA 的粘附能力。重要的是，胶原诱导性关节炎模型表明，关节内注射 DHY 可以显著降低炎症细胞因子的表达并缓解 RA 症状，而与甲氨蝶呤联合使用可以显著改善。在这里，通过不断降解 NETs 的新型药物靶点，开发了一种用于 RA 治疗的 DNase 功能化水凝胶，以减少 RA 中的炎症反应。
