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.

持续关节内递送疾病修饰性骨关节炎药物（DMOADs）有望预防