Intra-Articular Delivery of Sustained Release NF-kB Antagonists in Arthritis

膝关节、髋关节或脚踝的损伤或损伤是关节过早发作的一个公认的因素。 退行性骨关节炎(OA)。核因子kappaB(NF-B)是一种早期表达的转录因子。 激活细胞外基质分解代谢和关节相关基因参与创伤后骨性关节炎 发炎。核因子-B活性升高也与关节损伤后疼痛的发生有关 以及其他肌肉骨骼病变。尽管有许多化合物可以抑制核因子-B， 通过全身给药甚至局部给药来抑制NF-B到关节的药物治疗尚未见报道 在治疗骨性关节炎方面取得了成功。我们假设核因子-B拮抗剂的关节内注射来自 一种安全、缓释的载体(丝绸)在减轻疼痛相关的敏感性、关节 非手术的骨关节炎关节内骨折模型中的功能障碍和进行性关节病理学。我们 之前在一个模型中发现了NF-B活性与疼痛相关敏感性之间的强烈相关性 炎性关节损伤采用NF-B-荧光素酶报告小鼠。在这里，我们将类似地跟踪NF-B的活动， 但在闭合性胫骨骨折的小鼠模型中，作为关节损伤的非手术模型，这是已知的进展 干杯。在特定目标1中，我们将评估NF-B活性的时空发展，疼痛- 小鼠关节内骨折8周后的相关敏感性和关节功能障碍。我们会 确定全身和局部NF-B激活、敏感度、步态和体重之间的关系- 关节骨折后的轴承和关节炎进展。结果将确定治疗时机的“治疗窗口” 靶向关节内给药3.靶向优化丝素蛋白微粒 用于缓释两种小分子核因子-B抑制剂SC-514或PHA-408的仓库。我们有 先前证实，丝素蛋白微粒在被输送到关节时停留时间延长 空间，但还没有纳入药物进行缓释。丝素蛋白微粒(10-60微米)将被 针对每个核因子-B抑制剂制造，并进行测试以验证高载药量和缓释至4 几周。在特定的目标3中，我们将评估单次关节内注射SC-514或PHA-408 丝素微粒可减弱核因子-B活化、疼痛相关敏感性、关节功能障碍、 关节内骨折后的关节病理改变。关节内注射载药微粒将 在受伤后早期或晚期给予受伤肢体，并对效果进行纵向监测 关于核因子-B的激活、疼痛相关敏感性、关节功能障碍和关节炎的发展。结果将揭示 无论是哪种化合物，以及在什么时候，都可以调节关节炎症状的明确结果测量 和/或此模型中的病理进展。这项工作将建立一个安全、持续的发布策略 对于OA的局部治疗，可以提高整个小分子NF-B的实用性 治疗骨性关节炎患者的病理和/或疼痛发展的高可能性拮抗剂。

Injury or trauma to the knee, hip, or ankle is a well-documented contributor to premature onset of joint degeneration and osteoarthritis (OA). Nuclear factor kappa B (NF-B) is a transcription factor that has early involvement in post-traumatic OA by activating genes involved in extracellular matrix catabolism and joint inflammation. Increased NF-B activity has also been implicated in the development of pain following joint injury and other musculoskeletal pathologies. Despite the availability of numerous compounds that inhibit NF-B, pharmacologic inhibition of NF-B via systemic administration or even local delivery to the joint has not been successful in the treatment of OA. We hypothesize that intra-articular delivery of NF-B antagonists from a safe, sustained-release carrier (silk) will have value in attenuating pain related sensitivities, joint dysfunction, and progressive joint pathology in a non-surgical, intra-articular fracture model of OA. We have previously identified a strong correlation between NF-B activity and pain-related sensitivity in a model of inflammatory joint injury using the NF-B-luciferase reporter mouse. Here, we will similarly track NF-B activity, but in a mouse model of closed tibial fracture as a non-surgical model of joint injury which is known to progress to OA. In Specific Aim 1, we will evaluate the temporal and spatial development of NF-B activity, pain- related sensitivities, and joint dysfunction in mice following intra-articular fracture out to 8 weeks. We will identify relationships between systemic and local NF-B activation, patterns for sensitivity, gait and weight- bearing, and arthritis progression following joint fracture. Results will identify “therapeutic windows” for timing of intra-articular drug delivery in Specific Aim 3. In Specific Aim 2, we will optimize silk fibroin microparticle depots for sustained release of two small molecule NF-B inhibitors, SC-514 or PHA-408. We have previously demonstrated increased residence times for silk fibroin microparticles when delivered to the joint space, but have not incorporated a drug for sustained release. Silk fibroin microparticles (10-60 microns) will be fabricated specific to each NF-B inhibitor, and tested to verify high drug loading and sustained release out to 4 weeks. In Specific Aim 3, we will evaluate if a single, intra-articular injection of SC-514 or PHA-408-loaded silk fibroin microparticles can attenuate NF-B activation, pain-related sensitivities, joint dysfunction, and joint pathology after intra-articular fracture. Intra-articular injections of drug-loaded microparticles will be administered to the injured limb at either early or late times after injury, with longitudinal monitoring of effects on NF-B activation, pain-related sensitivities, joint dysfunction and arthritis development. Results will reveal whether either compound, and at which time, can modulate defined outcome measures of arthritis symptoms and/or pathology progression in this model of OA. This work will establish a safe, sustained release strategy for the local treatment of OA that can advance utility for an entire class of small molecule NF-B antagonists with a high likelihood for treating pathology and/or pain development in patients with OA.