This study aimed to formulate nanocrystal-polymer particles (NPPs) containing the potent p38α/β MAPK inhibitor PH-797804 (PH-NPPs) and to test their extended-release properties over months in comparison to those of conventional PH microparticles for the intra-articular treatment of inflammatory and mechanistic murine models mirroring aspects of human osteoarthritis (OA). The steps of the study were (i) to formulate PH nanocrystals (wet milling), (ii) to encapsulate a high payload of PH nanocrystals in fluorescent particles (spray drying), (iii) to assess in vitro drug release, (iv) to evaluate PH-NPP toxicity to human OA synoviocytes (MTT test), (v) to investigate the in vivo bioactivity of the particles in mice in an inflammatory antigen-induced arthritis (AIA) model (using histology and RT-qPCR) and (vi) to investigate the in vivo bioactivity of the particles in the OA model obtained by mechanistic surgical destabilization of the medial meniscus (DMM) (using histology, micro-CT, and multiplex ELISA). The PH nanocrystals stabilized with vitamin E TPGS had a monomodal size distribution. The PH-NPPs had a mean diameter of 14.2 μm and drug loading of ~31.5% (w/w), and ~20% of the PH was released over 3 months. The NPPs did not exhibit toxicity to cultured human OA synoviocytes at 100 × IC₅₀. Finally, in vivo studies showed good retention of PH-NPPs in the joint and adjacent tissues for up to 2 months, and the PH-NPPs exhibited good functional relevance by significantly reducing inflammation and joint destruction and by inhibiting several biomarkers (e.g., IL-1β). In conclusion, local treatment with PH-NPPs, used as an extended-release drug delivery system, improved inflammation and joint degradation in two distinct mouse models, indicating treatment potential for human OA.

这项研究旨在配制含有强效p38α/βMAPK抑制剂PH-797804（PH-NPPs）的纳米晶体聚合物颗粒（NPPs），并测试其与常规PH微粒相比在几个月内的缓释性能。炎性和机械性小鼠模型的关节治疗反映了人类骨关节炎（OA）的各个方面。研究的步骤是（i）配制PH纳米晶体（湿磨），（ii）将高有效载荷的PH纳米晶体封装在荧光颗粒中（喷雾干燥），（iii）评估体外药物释放，（iv）评估PH-NPP对人OA滑膜细胞的毒性（MTT试验），（v）研究体内炎症性抗原诱导的关节炎（AIA）模型中小鼠体内颗粒的生物活性（使用组织学和RT-qPCR）和（vi）研究内侧模型的机械性去稳定作用获得的OA模型中颗粒的体内生物活性半月板（DMM）（使用组织学，微型CT和多重ELISA）。用维生素E TPGS稳定的PH纳米晶体具有单峰尺寸分布。PH-NPP的平均直径为14.2μm，载药量约为31.5％（w / w），并且在3个月内释放了约20％的PH。NPP在100×IC _50下对培养的人OA滑膜细胞没有毒性。最后，体内研究表明，PH-NPPs在关节和邻近组织中的保留时间长达2个月，并且通过显着减少炎症和关节破坏并抑制多种生物标志物（例如IL-1β），PH-NPPs具有良好的功能相关性。总之，PH-NPPs的局部治疗（用作缓释药物递送系统）在两种不同的小鼠模型中改善了炎症和关节降解，表明对人OA的治疗潜力。