A self-assembled hydrogel with tunable drug release kinetics for preventing osteoarthritis in active joints

具有可调节药物释放动力学的自组装水凝胶，用于预防活动关节中的骨关节炎

• 批准号: 10397140
• 负责人: Nitin Joshi
• 金额: $ 37.66万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397140
• 关键词: Address; Ally; Animals; Biological; Biological Products; Clinical Trials; Data; Degenerative polyarthritis; Development; Disease; Drug Delivery Systems; Drug Kinetics; Encapsulated; Engineering; Enzymes; Esters; Exhibits; Formulation; Future; Genes; Goals; Human; Hydrogels; In Vitro; Joints; Kinetics; Knee joint; Knowledge; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Mission; Mus; Outcome; Pathology; Patients; Pharmaceutical Preparations; Preparation; Prevention; Process; Property; Public Health; Recovery; Reporting; Research; Rotation; Running; Solvents; System; Therapeutic; Therapeutic Effect; Time; Translations; Treatment Efficacy; United States National Institutes of Health; Variant; anakinra; base; cathepsin K; clinical translation; disability; drug efficacy; drug release kinetics; esterase; evidence base; fibroblast growth factor 18; healing; inhibitor; innovation; joint loading; mechanical load; novel; novel therapeutics; overexpression; prevent; residence; small molecule; tool; treadmill; viscoelasticity

Sustained intra-articular delivery of disease modifying osteoarthritis drugs (DMOADs) holds promise for preventing the progression of osteoarthritis (OA). However, since (DMOADs) are intended for early OA, when patients are active, repeated mechanical loading of joints can be detrimental to the delivery system, causing rapid drug release. To our knowledge, none of the previously reported intra-articular platforms for DMOAD delivery have been evaluated in physically active animals or have considered the impact of activity induced mechanical stress on the delivery platform and the drug release. We have developed a hydrogel platform that can rapidly recover following mechanical stress relevant to running human knee joints, with no impact on sustained release of the encapsulated agents. Hydrogel loaded with cathepsin-K inhibitor (L-006235) – a small molecule DMOAD prevented OA progression in mice undergoing treadmill running. The overall objective of this application are to (i) develop variants of our hydrogel platform with different release kinetics of L-006235 to understand how local release kinetics/pharmacokinetics impacts therapeutic efficacy and (ii) further engineer the hydrogel platform for delivery of biologic DMOADs. Our long-term goal is to develop a versatile and mechanically stable drug delivery platform with tunable release kinetics for intra-articular delivery of DMOADs in active joints to prevent OA progression. Our central hypothesis is that a mechanically stable hydrogel platform can minimize the impact of joint-related mechanical stress on sustained release of DMOADs and therapeutic efficacy of this system can be maximized by tuning the local release kinetics of DMOADs. To achieve our objectives, we propose two specific aims: 1) Investigate the impact of release kinetics of L-006235 on therapeutic efficacy; and 2) Investigate the delivery of biologic DMOADs in active joints using hydrogel. Under the first aim, we will develop hydrogel variants with different release kinetics of L-006235 and will study the impact of mechanical stress relevant to human joints on hydrogel variants and L-006235 release. Next, we will validate the differences in release kinetics in treadmill running mice and evaluate the therapeutic efficacy and off-target effects in treadmill running mice with OA. For the second aim, we will identify formulation parameters, including TG-18 concentration and choice of solvent to maximize loading and stability of three different biologic DMOADs (IL-1Ra, FGF-18 and sTNFRII). Formulations will be evaluated for mechanical stability in vitro, release kinetics in treadmill running mice and efficacy and off-target effects in treadmill running mice with OA. The research proposed in this application is innovative, in our opinion, because it focuses on a novel hydrogel platform that is mechanically stable in joints, allows tunability of release kinetics and is versatile. We will be the first to (i) demonstrate therapeutic efficacy of a wide range of DMOADs in “physically active joints” and (ii) demonstrate that release kinetics of DMOADs defines their therapeutic efficacy. The proposed research is significant because it is expected to provide strong scientific justification for continued development and future clinical trials of this promising hydrogel that will enable us and others to compare the effect of different DMOADs on OA pathology in active joints, and identify the most promising DMOADs and their ideal release kinetics. Ultimately, such knowledge has the potential to offer paradigm shifting impact in OA therapy by enabling translation of promising DMOADs.

修饰骨关节炎药物（DMOADS）的持续关节内分娩有望防止 骨关节炎（OA）的进展。但是，由于（DMOADS）用于早期OA，因此患者是 可以确定接头的主动，重复的机械加载到输送系统，从而导致快速药物 发布。据我们所知，先前报道的DMOAD交付的关节内平台都没有 在身体活跃的动物中进行了评估，或者考虑了活性引起的机械的影响 交付平台和药物释放的压力。我们已经开发了一个可以迅速的水凝胶平台 在与运行人膝关节相关的机械压力之后恢复，对持续 释放封装药物。载有组织蛋白酶-K抑制剂的水凝胶（L-006235） - 一个小分子 DMOAD阻止了经历跑步机的小鼠的OA进展。总体目标 应用于（i）使用L-006235的不同释放动力学开发水凝胶平台的变体 了解本地释放动力学/药代动力学如何影响热效率，并且（ii）进一步的工程师 用于传递生物DMOADS的水凝胶平台。我们的长期目标是开发一种多功能和 机械稳定的药物输送平台，具有可调释放动力学，用于DMOADS的关节内输送 在主动关节中以防止OA进展。我们的中心假设是机械稳定的水凝胶 平台可以最大程度地减少与联合相关的机械应力对DMOADS持续释放的影响 通过调整DMOADS的局部释放动力学，该系统的治疗效率可以最大化。到 实现我们的目标，我们提出了两个具体目标：1）研究L-006235释放动力学的影响 关于热效率； 2）研究使用水凝胶在活性关节中的生物DMOAD递送。 在第一个目标下，我们将开发具有L-006235不同释放动力学的水凝胶变体，并将研究 与人关节相关的机械应力对水凝胶变体和L-006235释放的影响。接下来，我们 将验证运行小鼠跑步机的释放动力学差异并评估治疗效率 以及与OA一起运行小鼠的跑步机的脱靶效应。对于第二个目标，我们将确定公式 参数，包括TG-18浓度和解决方案的选择，以最大程度地提高加载和稳定性三个 不同的生物DMOADS（IL-1RA，FGF-18和STNFRII）。将评估配方的机械 体外稳定性，在跑步机中释放动力学以及跑步机的有效性和脱靶效应 带有OA的老鼠。在我们看来，在本应用程序中提出的研究具有创新性，因为它的重点是 新型水凝胶平台在关节中机械稳定，允许释放动力学的可鼠能力，并且IS 多才多艺的。我们将是（i）第一个在物理上表现出广泛DMOADS的治疗效率 主动关节”和（ii）表明，释放DMOADS的动力学定义了它们的治疗效率。 拟议的研究很重要，因为它有望为持续提供强大的科学依据 这种有希望的水凝胶的开发和未来临床试验将使我们和其他人比较 不同DMOADS对活性关节中OA病理的影响，并确定最有希望的DMOADS和 他们理想的释放动力学。最终，这种知识有可能在OA中提供范式转移影响 通过启用承诺DMOADS的翻译来治疗。