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创伤是关节炎过早发作的一个有据可查的因素。 退行性变和骨关节炎（OA）。核因子κ B（NF-κ B B）是一种转录因子， 通过激活参与细胞外基质软骨和关节的基因参与创伤后OA 炎症增加的NF-κ B B活性也与关节损伤后疼痛的发展有关 和其他肌肉骨骼疾病。尽管有许多抑制NF-κ B B的化合物， 通过全身给药或甚至局部递送至关节的NF-κ B B的药理学抑制尚未被 成功治疗OA。我们假设，关节内注射NF-κ B B拮抗剂， 安全、缓释的载体（丝绸）将在减轻与疼痛相关的敏感性、关节方面具有价值 功能障碍和进行性关节病理学。我们 先前已经在一个模型中确定了NF-κ B B活性和疼痛相关敏感性之间的强相关性， 使用NF-κ B-荧光素酶报告小鼠观察炎性关节损伤。在这里，我们将类似地跟踪NF-κ B B活性， 但在小鼠闭合性胫骨骨折模型中，作为关节损伤的非手术模型， 到OA。在具体目标1中，我们将评估NF-κ B B活性、疼痛和神经功能的时间和空间发展。 相关的敏感性，和关节功能障碍的小鼠关节内骨折后8周。我们将 确定全身和局部NF-κ B B激活、敏感性模式、步态和体重之间的关系， 关节骨折后关节炎进展。结果将确定“治疗窗口”， Specific Aim 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 用于持续释放两种小分子NF-κ B B抑制剂SC-514或PHA-408的贮库。我们有 先前证明丝纤蛋白微粒在递送至关节时的停留时间增加 空间，但没有纳入持续释放的药物。丝纤蛋白微粒（10-60微米）将被 制造的特定于每一种NF-κ B B抑制剂，并进行测试，以验证高载药量和持续释放到4 周在特定目标3中，我们将评估单次关节内注射SC-514或PHA-408载药 丝纤蛋白微粒可减弱NF-κ B B活化、疼痛相关敏感性、关节功能障碍 和关节内骨折后的关节病理学。关节内注射载药微粒将 在受伤后的早期或晚期给予受伤肢体，并纵向监测效果 对NF-κ B B活化、疼痛相关敏感性、关节功能障碍和关节炎发展的影响。结果将揭示 无论是哪种化合物，以及在什么时候，可以调节关节炎症状的定义结果测量 和/或病理学进展。这项工作将建立一个安全，持续释放策略 对于OA的局部治疗，可以提高整个类别的小分子NF-κ B B的效用 具有治疗OA患者的病理学和/或疼痛发展的高可能性的拮抗剂。

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