Antiproliferative chemotherapeutic agents offer a potential effective treatment for inflammatory arthritis. However, their clinical application is limited by high systemic toxicity, low joint bioavailability as well as formulation challenges. Here, we report an intra-articular drug delivery system combining hyaluronic acid hydrogels and drug nanocrystals to achieve localized and sustained delivery of an antiproliferative chemotherapeutic agent camptothecin for long-term treatment of inflammatory arthritis. We synthesized a biocompatible, in situ-forming injectable hyaluronic acid hydrogel using a naturally occurring click chemistry: cyanobenzothiazole/cysteine reaction, which is the last step reaction in synthesizing D-luciferin in fireflies. This hydrogel was used to encapsulate camptothecin nanocrystals (size of 160–560 nm) which released free camptothecin in a sustained manner for 4 weeks. In vivo studies confirmed that the hydrogel remained in the joint over 4 weeks. By using the collagen-induced arthritis rat model, we demonstrate that the hydrogel-camptothecin formulation could alleviate arthritis severity as indicated by the joint size and interleukin-1β level in the harvested joints, as well as from histological and microcomputed tomography evaluation of joints. The hydrogel-nanocrystal formulation strategy described here offers a potential solution for intra-articular therapy for inflammatory arthritis.

中文翻译：

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可注射透明质酸水凝胶包封药物纳米晶体用于长期治疗炎症性关节炎

抗增殖化学治疗剂为炎性关节炎提供了潜在的有效治疗。然而，它们的临床应用受到高全身毒性、低联合生物利用度以及配方挑战的限制。在这里，我们报告了一种结合透明质酸水凝胶和药物纳米晶体的关节内药物递送系统，以实现抗增殖化学治疗剂喜树碱的局部和持续递送，用于长期治疗炎症性关节炎。我们使用自然发生的点击化学合成了一种生物相容的、原位形成的可注射透明质酸水凝胶：氰基苯并噻唑/半胱氨酸反应，这是合成D的最后一步反应-萤火虫中的萤光素。这种水凝胶用于封装喜树碱纳米晶体（大小为 160-560 nm），其以持续的方式释放游离喜树碱 4 周。体内研究证实，水凝胶在关节中保留超过 4 周。通过使用胶原蛋白诱导的关节炎大鼠模型，我们证明了水凝胶-喜树碱制剂可以减轻关节炎的严重程度，如关节大小和收获关节中的白细胞介素 1β 水平以及关节的组织学和微计算机断层扫描评估所示。这里描述的水凝胶纳米晶体配方策略为炎症性关节炎的关节内治疗提供了潜在的解决方案。