There is an increasing interest in controlled release systems for local therapy in the treatment of human and equine joint diseases, aiming for optimal intra-articular concentrations with no systemic side effects. In this study, the intra-articular tolerability and suitability for local and sustained release of tacrolimus (FK506) from monospheres composed of [PDLA-PEG₁₀₀₀]-b-PLLA multiblock copolymers were investigated. Unloaded and tacrolimus-loaded (18.4 mg tacrolimus/joint) monospheres were injected into the joints of six healthy horses, with saline and hyaluronic acid (HA) in the contralateral joints as controls. Blood and synovial fluid were analysed for the tacrolimus concentration and biomarkers for inflammation and cartilage metabolism. After an initial burst release, sustained intra-articular tacrolimus concentrations (>20 ng/mL) were observed during the 42 days follow-up. Whole-blood tacrolimus levels were below the detectable level (<0.5 ng/mL). A transient inflammatory reaction was observed for all substances, evidenced by increases of the synovial fluid white blood cell count and total protein. Prostaglandin and glycosaminoglycan release were increased in joints injected with unloaded monospheres, which was mitigated by tacrolimus. Both tacrolimus-loaded monospheres and HA transiently increased the concentration of collagen II cleavage products (C2C). A histologic evaluation of the joints at the endpoint showed no pathological changes in any of the conditions. Together, these results indicate the good biocompatibility of intra-articular applied tacrolimus-loaded monospheres combined with prolonged local drug release while minimising the risk of systemic side effects. Further evaluation in a clinical setting is needed to determine if tacrolimus-loaded monospheres can be beneficial in the treatment of inflammatory joint diseases in humans and animals.

中文翻译：

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由 [PDLA-PEG1000]-b-[PLLA] 多嵌段共聚物组成的他克莫司 (FK506) 负载单球在健康马关节中的持续关节内释放和生物相容性

人们对用于治疗人和马关节疾病的局部治疗的控释系统越来越感兴趣，目的是在没有全身副作用的情况下获得最佳的关节内浓度。在这项研究中，他克莫司 (FK506) 从由 [PDLA-PEG ₁₀₀₀ ]- b组成的单球体局部和持续释放的关节内耐受性和适用性研究了-PLLA多嵌段共聚物。将卸载的和装载他克莫司（18.4 毫克他克莫司/关节）的单球注射到六匹健康马的关节中，对侧关节中的盐水和透明质酸 (HA) 作为对照。分析血液和滑液的他克莫司浓度以及炎症和软骨代谢的生物标志物。在初始突释后，在 42 天的随访期间观察到持续的关节内他克莫司浓度 (>20 ng/mL)。全血他克莫司水平低于可检测水平 (<0.5 ng/mL)。对所有物质都观察到了短暂的炎症反应，表现为滑液白细胞计数和总蛋白增加。注射无负荷单球的关节中前列腺素和糖胺聚糖的释放增加，他克莫司可以缓解这种情况。装载他克莫司的单球和 HA 都瞬时增加了 II 型胶原裂解产物 (C2C) 的浓度。终点时关节的组织学评估显示，在任何情况下都没有病理变化。总之，这些结果表明关节内应用他克莫司负载的单球具有良好的生物相容性，结合延长的局部药物释放，同时最大限度地减少全身副作用的风险。需要在临床环境中进一步评估以确定他克莫司负载的单球是否有益于治疗人类和动物的炎性关节疾病。终点时关节的组织学评估显示，在任何情况下都没有病理变化。总之，这些结果表明关节内应用他克莫司负载的单球具有良好的生物相容性，结合延长的局部药物释放，同时最大限度地减少全身副作用的风险。需要在临床环境中进一步评估以确定他克莫司负载的单球是否有益于治疗人类和动物的炎性关节疾病。终点时关节的组织学评估显示，在任何情况下都没有病理变化。总之，这些结果表明关节内应用他克莫司负载的单球具有良好的生物相容性，结合延长的局部药物释放，同时最大限度地减少全身副作用的风险。需要在临床环境中进一步评估以确定他克莫司负载的单球是否有益于治疗人类和动物的炎性关节疾病。