School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, CH-1211, Geneva 4, Switzerland.
Department of Clinical Science, Idorsia Pharmaceuticals Ltd., CH-4123, Allschwil, Switzerland.
Small. 2018 Feb;14(8). doi: 10.1002/smll.201703108. Epub 2018 Jan 12.
An efficient treatment for osteoarthritis (OA) can benefit from the local release of a high therapeutic dose over an extended period of time. Such a treatment will minimize systemic side effects and avoid the inconvenience of frequent injections. To this aim, nanocrystal-polymer particles (NPPs) are developed by combining the advantages of nanotechnology and microparticles. Nanocrystals are produced by wet milling kartogenin (KGN), which is known to promote chondrogenesis and to foster chondroprotection. A fluorescent biodegradable polymer is synthesized for intravital particle tracking. Polymer microparticles with 320 nm embedded KGN nanocrystals (KGN-NPPs) show a high drug loading of 31.5% (w/w) and an extended drug release of 62% over 3 months. In vitro, these particles do not alter mitochondrial activity in cultured human OA synoviocytes. In vivo, KGN-NPPs demonstrate higher bioactivity than a KGN solution in a murine mechanistic OA model based on histological assessment (Osteoarthritis Research Society International score), epiphyseal thickness (microcomputed tomography), OA biomarkers (e.g., vascular endothelial growth factor, Adamts5), and prolonged intra-articular persistence (fluorescence analysis). This work provides proof-of-concept of a novel and innovative extended drug delivery system with the potential to treat human OA.
一种有效的骨关节炎（OA）治疗方法可以通过在较长时间内局部释放高治疗剂量来实现。这种治疗方法将最大限度地减少全身副作用，并避免频繁注射的不便。为此，通过结合纳米技术和微颗粒的优势，开发了纳米晶体-聚合物颗粒（NPPs）。通过湿磨法制备了原代蛋白聚糖基因酮（KGN）纳米晶体，已知其具有促进软骨生成和促进软骨保护的作用。合成了一种荧光可生物降解的聚合物，用于体内颗粒追踪。载有 320nm 嵌入 KGN 纳米晶体的聚合物微颗粒（KGN-NPPs）具有 31.5%（w/w）的高载药量和 3 个月以上的 62%的延长药物释放。在体外，这些颗粒不会改变培养的人 OA 滑膜细胞中的线粒体活性。在体内，基于组织学评估（骨关节炎研究协会国际评分）、骺板厚度（微计算机断层扫描）、OA 生物标志物（例如血管内皮生长因子、Adamts5）和延长的关节内持久性（荧光分析），KGN-NPPs 在基于机械的鼠 OA 模型中比 KGN 溶液显示出更高的生物活性。这项工作为一种新型创新的延长药物递送系统提供了概念验证，具有治疗人类 OA 的潜力。
