Intra-cartilage depot delivery of electrically-charged IL-1RA for targeting osteoarthritis-associated inflammation and catabolism in multiple joint tissues

软骨内储库递送带电 IL-1RA，用于靶向多个关节组织中与骨关节炎相关的炎症和分解代谢

• 批准号: 10471429
• 负责人: Ambika Goel Bajpayee
• 金额: $ 42.12万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471429
• 关键词: Acceleration; Adverse effects; Affect; Affinity; Anabolism; Arthritis; Avidin; Binding; Biochemical; Biodistribution; Biological; Biotinylation; Bone callus; Bovine Cartilage; Cartilage; Cartilage Matrix; Catabolism; Cell Survival; Cells; Charge; Clinical Trials; Coculture Techniques; Collagen; Confocal Microscopy; Degenerative polyarthritis; Diameter; Disease; Dose; Drug Carriers; Drug Delivery Systems; Drug Modulation; Drug or chemical Tissue Distribution; Effectiveness; Electrostatics; Engineering; Equilibrium; Fracture; Gene Expression; Genes; Glycoproteins; Glycosaminoglycans; Histology; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukins; Intervertebral disc structure; Intra-Articular Injections; Joints; Label; Mass Spectrum Analysis; Measures; Mediating; Meniscus structure of joint; MicroRNAs; Modeling; Modification; Organ; Oryctolagus cuniculus; Outcome; Penetration; Peptides; Pharmaceutical Preparations; Pre-Clinical Model; Property; Proteins; Proteomics; Radiolabeled; Rattus; Role; Site; Specificity; Structure; Synovial Fluid; Synovial Membrane; Synovial joint; Synovitis; Techniques; Testing; Therapeutic; Thick; Time; Tissues; Traumatic Arthropathy; Western Blotting; Work; anakinra; articular cartilage; biomechanical test; bone; cellular targeting; clinical effect; clinical translation; cytokine; density; design; driving force; drug clearance; effective therapy; exosome; extracellular; in vivo; inhibitor; joint injury; microCT; prevent; protein expression; residence; response; subchondral bone; systemic toxicity; targeted delivery; time use; tissue degeneration; uptake

Project Summary Despite the existence of promising osteoarthritis (OA) drugs, its treatment remains a challenge due to ineffective drug delivery systems. Intra-articular (IA) delivery is inadequate as drugs rapidly clear out from joint space and are unable to penetrate through the dense, negatively charged cartilage and reach their cell and matrix target sites at optimal concentrations. As a result, no disease modifying OA drugs (DMOADs) have passed clinical trials due to concerns of systemic toxicity and lack of cartilage targeting. For effective treatment, it is critical to stimulate a disease modifying biological response within multiple joint tissues, including cartilage, synovium and subchondral bone. Interleukin (IL)-1 receptor antagonist (IL-1RA) is proven to be a promising DMOAD for modulating both synovium inflammation and cartilage catabolism in preclinical models of post-traumatic (PT)OA; however, it has failed to show sustained clinical effect owing to lack of cartilage targeting and short joint residence time. The high negative charge density of cartilage provides a unique opportunity to use electrostatic interactions for enhancing uptake, depth of penetration, and retention of cationic drugs or drug carriers. We have shown that the cationic glycoprotein Avidin, owing to its optimal size and charge, was effective for intra-cartilage delivery as it rapidly penetrated through full thickness of cartilage in rats and rabbits following IA injection, resulting in 400- fold higher intra-cartilage uptake compared to its neutral counterpart and was retained inside cartilage for 3-4 weeks. Based on Avidin’s structure, we have designed a Cationic Peptide Carrier (CPC) that displayed similarly high uptake in both normal and glycosaminoglycan-depleted cartilage. This project will develop electrically charged IL-1RA by conjugating it with Avidin and CPC to make it cartilage penetrating and binding, thus increasing its tissue specificity and residence time. This way, cartilage can be converted from a barrier to drug entry into a drug depot, such that the anti-catabolic effects of charged IL-1RA in both cartilage and nearby synovium are significantly enhanced compared to unmodified IL-1RA. In Aim 1, Avidin-IL-1RA and CPC-IL-1RA will be characterized and their key transport properties (diffusivities, equilibrium uptakes, partitioning, binding constants) will be compared with unmodified IL-1RA in normal and arthritic cartilage. Aim 2 will evaluate the biological efficacy of a single dose of charged IL-1RA for inhibiting cytokine induced catabolism in a cartilage- synovium co-culture OA model, comparing Avidin/CPC-IL-1RA conjugates with single and continuous dose of unmodified IL-1RA. Aim 3 will determine the therapeutic potential of a single IA injection of charged IL-1RA relative to unmodified IL-1RA using a rabbit PTOA model. This work will advance the field of charge based drug delivery in targeting multiple joint tissues for effective, holistic OA treatment by applying fundamental concepts of bio-electrostatics and bio-transport. This charge-based platform can be used for delivering a wide range of drugs to other tissues with similar properties, such as meniscus, intervertebral disc and fracture callus, and also enable clinical translation of various OA drugs that have failed clinical trials due to lack of tissue targeting.

项目概要 尽管存在有前景的骨关节炎（OA）药物，但由于疗效不佳，其治疗仍然是一个挑战 由于药物迅速从关节间隙中清除，因此关节内 (IA) 的药物输送系统不充分。 无法穿透致密、带负电的软骨并到达细胞和基质目标 因此，没有任何疾病修饰 OA 药物 (DMOAD) 已通过临床。 由于担心全身毒性和缺乏软骨靶向，因此进行试验对于有效治疗至关重要。 刺激多个关节组织内的疾病改变生物反应，包括软骨、滑膜和 软骨下骨。白细胞介素 (IL)-1 受体拮抗剂 (IL-1RA) 被证明是一种有前途的 DMOAD。 在创伤后 (PT)OA 的临床前模型中调节滑膜炎症和软骨分解代谢； 然而，由于缺乏软骨靶向和关节停留时间短，它未能显示出持续的临床效果 软骨的高负电荷密度提供了利用静电相互作用的独特机会。 我们已经证明，增强阳离子药物或药物载体的吸收、渗透深度和保留。 阳离子糖蛋白亲和素由于其最佳的大小和电荷，对于软骨内递送是有效的 在注射 IA 后，它迅速渗透到大鼠和兔子的整个软骨层，导致 400- 与中性对应物相比，软骨内摄取高出一倍，并在软骨内保留 3-4 倍 基于亲和素的结构，我们设计了具有类似表现的阳离子肽载体（CPC）。 正常软骨和糖胺聚糖耗尽软骨中的高吸收该项目将开发电力。 通过与Avidin和CPC结合使IL-1RA带电，使其穿透软骨并结合，从而 增加其组织特异性和停留时间，软骨可以从屏障转变为药物。 进入药物仓库，使得带电 IL-1RA 在软骨和附近的抗分解代谢作用 与未修饰的 IL-1RA 相比，Aimin-IL-1RA 和 CPC-IL-1RA 的滑膜显着增强。 将被表征及其关键传输特性（扩散性、平衡吸收、分配、结合 常数）将与正常软骨和关节炎软骨中未修饰的 IL-1RA 进行比较，目标 2 将评估 单剂量带电 IL-1RA 抑制软骨中细胞因子诱导的分解代谢的生物学功效 滑膜共培养 OA 模型，比较抗生物素蛋白/CPC-IL-1RA 缀合物与单剂量和连续剂量的 目标 3 将确定单次 IA 注射带电 IL-1RA 的治疗潜力。 相对于未修饰的 IL-1RA，使用兔 PTOA 模型这项工作将推进基于电荷的药物领域。 通过应用基本概念，针对多个关节组织进行有效、整体的 OA 治疗 这种基于电荷的平台可用于提供广泛的生物静电和生物传输。 与药物性质相似的其他组织，如半月板、椎间盘和骨折愈伤组织，以及 使各种因缺乏组织靶向而未能通过临床试验的 OA 药物能够进行临床转化。