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

持续关节内递送疾病缓解骨关节炎药物（DMOAD）有望预防 骨关节炎（OA）的进展。然而，由于（DMOAD）预期用于早期OA，当患者 关节的主动、重复的机械负荷可能对递送系统有害， release.据我们所知，之前报道的用于DMOAD输送的关节内平台均未 在体力活动动物中进行了评价，或考虑了活动诱导的机械 对输送平台和药物释放的应力。我们开发了一种水凝胶平台， 恢复后的机械应力有关的运行人类膝关节，没有影响持续 释放包封的试剂。负载组织蛋白酶-K抑制剂（L-006235）的水凝胶-一种小分子 DMOAD阻止了小鼠在跑步机上跑步时OA的进展。本报告的总体目标 （i）开发具有不同L-006235释放动力学的我们的水凝胶平台的变体， 了解局部释放动力学/药代动力学如何影响治疗效果，以及（ii）进一步设计 用于递送生物DMOAD的水凝胶平台。我们的长期目标是开发一个多功能和 用于关节内递送DMOAD的具有可调释放动力学的机械稳定的药物递送平台 以防止OA进展。我们的中心假设是机械稳定的水凝胶 平台可以最大限度地减少关节相关机械应力对DMOAD持续释放的影响， 通过调节DMOAD的局部释放动力学可以使该系统的治疗功效最大化。到 为了实现我们的目标，我们提出了两个具体目标：1）研究L-006235释放动力学的影响 2）研究使用水凝胶在活动关节中递送生物DMOAD。 在第一个目标下，我们将开发具有不同L-006235释放动力学的水凝胶变体，并将研究 与人体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 将验证跑台小鼠中释放动力学的差异并评估治疗功效 和脱靶效应。对于第二个目标，我们将确定公式 参数，包括TG-18浓度和溶剂的选择，以最大限度地提高三个负载和稳定性 不同的生物DMOAD（IL-1 Ra、FGF-18和sTNFRII）。将评价制剂的机械性能 体外稳定性、在跑台小鼠中的释放动力学以及在跑台中的功效和脱靶效应 OA小鼠在我们看来，这项申请中提出的研究是创新的，因为它关注的是一个 一种新型水凝胶平台，其在关节中机械稳定，允许释放动力学的可调节性， 多才多艺我们将是第一个（i）证明各种DMOAD在“物理”治疗中的疗效 活动关节”和（ii）证明DMOAD的释放动力学决定了它们的治疗功效。的 拟议的研究是重要的，因为它预计将提供强有力的科学理由，继续 这种有前途的水凝胶的开发和未来的临床试验，将使我们和其他人能够比较 不同DMOAD对活动关节OA病理学的影响，并确定最有前途的DMOAD， 它们理想的释放动力学最终，这些知识有可能在OA中提供范式转变的影响 通过翻译有前景的DMOAD来治疗。

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.