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

持续关节内给药(DMOADs)有望预防 骨性关节炎的进展。然而，由于(DMOADs)是为早期OA设计的，当患者 关节的主动、反复的机械负荷可能对输送系统有害，导致药物迅速释放。 放手。据我们所知，之前报道的用于DMOAD交付的关节内平台中没有一个 在体力活动的动物身上进行过评估，或考虑过运动诱导的机械影响 重点放在给药平台和药物释放上。我们已经开发了一种水凝胶平台，可以快速 恢复与跑人膝关节有关的机械应力，不影响持续 包封剂的释放。组织蛋白酶-K抑制剂水凝胶(L-006235)--小分子 DMOAD阻止了跑步机跑步小鼠的骨性关节炎进展。这样做的总体目标是 应用是(I)开发我们的水凝胶平台的变体，具有不同的释放动力学L-006235到 了解局部释放动力学/药物动力学如何影响治疗效果和(Ii)进一步设计 用于输送生物DMOADs的水凝胶平台。我们的长期目标是开发一种多功能和 具有可调释放动力学的机械稳定的DMOADs关节内给药平台 在活跃的关节，以防止骨关节炎的进展。我们的中心假设是一种机械稳定的水凝胶 平台可将关节相关机械应力对DMOADs持续释放的影响降至最低 该系统的治疗效果可以通过调节DMOADs的局部释放动力学来最大化。至 为了实现我们的目标，我们提出了两个具体的目标：1)考察对L-006235释放动力学的影响 2)研究生物DMOADs在活动关节内的水凝胶给药情况。 在第一个目标下，我们将开发L-006235不同释放动力学的水凝胶变体，并将研究 人体关节相关机械应力对水凝胶变体和L-006235释放的影响。接下来，我们 将验证跑步机跑步小鼠在释放动力学上的差异，并评估治疗效果 以及在跑步机上跑步的患有骨性关节炎的小鼠的脱靶效应。对于第二个目标，我们将确定公式 参数，包括TG-18浓度和溶剂的选择，以最大限度地加载和稳定性三个 不同的生物DMOADs(IL-1ra、FGF18和sTNFRII)。将对配方进行机械评估 跑台跑小鼠的体外稳定性、释药动力学及跑台跑的疗效和靶外效应 患有骨性关节炎的小鼠。在本申请中提出的研究是创新的，在我们看来，因为它集中在 新型水凝胶平台，在关节中机械稳定，允许释放动力学可调，并 多面手。我们将是第一个(I)证明广泛的DMOAD的治疗效果在“身体” 活动关节“和(Ii)表明DMOADs的释放动力学决定了它们的治疗效果。这个 拟议的研究意义重大，因为预计它将为继续 这种前景看好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DMOADs对活动关节骨关节炎病理的影响，并确定最有前景的DMOADs和 它们理想的释放动力学。归根结底，这样的知识有可能在办公自动化中提供范式转换的影响 通过翻译有希望的DMOADs进行治疗。

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.