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

关节内缓释 NF-kB 拮抗剂治疗关节炎

• 批准号: 10092120
• 负责人: Lori A. Setton
• 金额: $ 32.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092120
• 关键词: Acute; Affect; Afferent Neurons; Ankle; Arthritis; Attenuated; Behavioral; Catabolism; Cell Death; Chronic; Clinical; Collaborations; Control Groups; Degenerative polyarthritis; Development; Drug Delivery Systems; Etiology; Extracellular Matrix; Fibroins; Formulation; Fracture; Functional disorder; Gait; Gene Activation; Genes; Hip region structure; Histology; Hydrophobicity; I Kappa B-Alpha; Image; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injury; Intra-Articular Injections; Joints; Knee; Luciferases; Measures; Mechanics; Microspheres; Modeling; Monitor; Mus; Musculoskeletal; NF-kappa B; NF-kappaB-inducing kinase; Nerve Growth Factors; Nociception; Outcome; Outcome Measure; Pain; Pathogenesis; Pathology; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Recording of previous events; Reporter; Role; Silk; Spinal Ganglia; Substance P; Symptoms; Synovitis; Testing; Therapeutic; Tibial Fractures; Time; Tissues; Trauma; Universities; Weight-Bearing state; Work; aqueous; base; cytokine; disability; drug testing; improved; in vivo; inhibitor/antagonist; joint destruction; joint function; joint inflammation; joint injury; limb injury; luminescence; lymph nodes; molecular marker; mouse model; physical property; premature; residence; small molecule; symptom treatment; transcription factor; treatment strategy

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.

膝关节、髋关节或踝关节的损伤或外伤是导致关节过早发作的一个有据可查的因素 核因子 kappa B (NF-κB) 是一种早期发生退化的转录因子。 通过激活参与细胞外基质分解代谢和关节的基因参与创伤后 OA 炎症中 NF-κB 活性的增加也与关节损伤后疼痛的发生有关。 尽管有许多化合物可以抑制 NF-κB， 通过全身给药或什至局部递送至关节来抑制 NF-κB 的药理作用尚未被证实。 我们勇敢地通过关节内递送 NF-κB 拮抗剂治疗 OA。 安全、持续释放的载体（丝绸）将具有减轻疼痛相关的敏感性、关节疼痛的价值。 OA 非手术关节内骨折模型中的功能障碍和进行性关节病理学。 先前已经在模型中发现 NF-κB 活性与疼痛相关敏感性之间存在很强的相关性。 使用 NF-β-荧光素酶报告小鼠观察炎症性关节损伤 在这里，我们将类似地追踪 NF-β 活性， 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，已知该模型会进展 在具体目标 1 中，我们将评估 NF-κB 活性、疼痛的时间和空间发展。 我们将在关节内骨折后 8 周内观察小鼠的相关敏感性和关节功能障碍。 确定全身和局部 NF-κB 激活、敏感性模式、步态和体重之间的关系 结果将确定关节骨折后的“治疗窗口”。 具体目标3中的关节内药物递送。在具体目标2中，我们将优化丝素蛋白微粒 我们有两种小分子 NF-κB 抑制剂 SC-514 或 PHA-408 的缓释制剂。 先前证明丝素蛋白微粒在输送到关节时的停留时间有所增加 空间，但未掺入缓释药物。丝素蛋白微粒（10-60微米）将是。 针对每种 NF-κB 抑制剂专门制造，并进行测试以验证高载药量和持续释放高达 4 在具体目标 3 中，我们将评估是否单次关节内注射 SC-514 或 PHA-408。 丝素蛋白微粒可以减弱 NF-κB 激活、疼痛相关的敏感性、关节功能障碍、 关节内骨折后的关节病理学。 在受伤后的早期或晚期对受伤的肢体进行治疗，并纵向监测效果 关于 NF-κB 激活、疼痛相关敏感性、关节功能障碍和关节炎发展的结果将揭示。 任一化合物是否以及在何时可以调节关节炎症状的确定结果指标 和/或该 OA 模型中的病理进展这项工作将建立一种安全、持续释放的策略。 用于 OA 的局部治疗，可提高一整类小分子 NF-κB 的效用 拮抗剂很有可能治疗 OA 患者的病理和/或疼痛发展。

项目成果

Intraarticularly injectable silk hydrogel microspheres with enhanced mechanical and structural stability to attenuate osteoarthritis.

• DOI: 10.1016/j.biomaterials.2022.121611
• 发表时间: 2022-05
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Tao Wang;Yuqi Li;Jian Liu;Y. Fang;Wen-jun Guo;Yu Liu;Xiangyu Li;Gang Li;Xiuli Wang