The Conundrum of Absentee Receptors: Efficacy Potentiation Through Drug-Receptor Modulation

项目总结/摘要 该提案概述了一种先进的药物输送方法，论证了生物治疗的力量， 通过受体上调证实了增加的biflazone功效。特异性的好处是 靶向生物治疗固有的缺陷是以基于同源受体的预期疗效为代价的 以足够高的密度存在以达到治疗效果。运载系统的当前进展 能够局部和延长药物释放。然而，定位只是有效药物的一个组成部分 局在这里，我们提出了一种先进的药物输送系统，合理设计，以加强药物 活性，同时定位和延长生物素浓度。作为临床相关的 例如，该提案概述了天然抗纤维化肽的协调定位和增强作用 激素松弛素-2（RLX）及其受体RXFP 1，用于治疗肩关节挛缩的根本原因 并恢复关节活动范围。RLX通过上调细胞外基质（ECM）蛋白质 金属蛋白酶（MMPs）和降低胶原蛋白水平。我们最近有了令人兴奋的发现， 地塞米松（DEX）增加了RXFP 1在纤维化滑膜细胞中的表达，并进一步探讨了RXFP 1在纤维化滑膜细胞中的作用。 RLX和DEX作用的分子机制将有助于药物设计的合理化。我们将检验这个假设 通过局部单一关节内（IA） 注射到滑膜间隙，将迅速缓解关节纤维化症状（关节僵硬增加， 活动范围减少（ROM）并减少受累关节中的纤维化组织积聚。此外，DEX 增强RLX的抗纤维化活性将降低最小有效剂量，并通过以下方式提高恢复率： 调节RXFP 1受体密度。该提案的成功完成将提供一种新的治疗方法， 关节纤维化，一种使人衰弱的疾病，在美国影响超过1500万人， 证明了递送生物素同时也增加靶受体密度的重要性 以最大限度地发挥功效。重要的是，重要的初步数据支持拟议的研究， 材料和严格的实验设计建立，必要的跨学科合作， 我们有专门知识来解决这些假设。这一五年建议的具体目标如下。 目的1确定RLX的配体-受体结合机制以及TGF-β1和DEX在调节细胞凋亡中的新作用。 RXFP 1表达，以及RLX的抗纤维化作用机制。目标2确定材料属性 表2显示了负载有DEX或RLX的生物可降解和生物相容性聚合物MP的特征。目标3 评价了最佳DEX MP + RLX MP联合给药制剂鸡尾酒的药代动力学和疗效 使用建立的体内肩挛缩模型在目标2中鉴定。

PROJECT SUMMARY/ABSTRACT This proposal outlines an advanced drug delivery methodology, argues for the power of biotherapeutics, and demonstrates increased biotherapeutic efficacy through receptor upregulation. The benefit of specificity that is inherent to targeted biotherapeutics comes at the cost of predicated efficacy based on the cognate receptor being present at a high enough density to achieve a therapeutic effect. Current advances in delivery systems are enabling localized and prolonged drug release. However, localization is only one component of effective drug administration. Here, we propose an advanced drug delivery system, rationally designed to potentiate drug activity while simultaneously localizing and prolonging biotherapeutic concentration. As a clinically relevant example, this proposal outlines the coordinated localization and potentiation of the natural antifibrotic peptide hormone, relaxin-2 (RLX), and its receptor, RXFP1, to both treat the underlying causes of shoulder contracture and to restore joint range of motion. RLX remodels extracellular matrix (ECM) proteins via upregulating matrix metalloproteases (MMPs) and decreasing collagen levels. We recently made the exciting discovery that dexamethasone (DEX) increases RXFP1 expression in fibrotic synoviocytes and further exploration of the molecular mechanism of actions of RLX and DEX will enhance rational drug design. We will test the hypothesis that co-administration of RLX and DEX from polymeric microparticles (MPs) via a local single intraarticular (IA) injection into the synovial space, will rapidly alleviate arthrofibrosis symptoms (increased joint stiffness and decreased range of motion, ROM) and reduce fibrotic tissue accumulation in the afflicted joint. Further, DEX potentiation of RLX’s antifibrotic activity will decrease the minimum effective dose and increase recovery rate by modulating RXFP1 receptor density. Successful completion of this proposal will provide a novel treatment for arthrofibrosis, a debilitating condition which affects more than 15 million people in the United States, and demonstrate the importance of both delivering a biotherapeutic while also increasing the target receptor density to maximize efficacy. Importantly, significant preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise are in place to address these hypotheses. The specific aims of this five-year proposal are as follows. Aim 1 determines RLX’s ligand-receptor binding mechanics and the novel role of TGF-β1 and DEX in regulating RXFP1 expression, as well as RLX’s antifibrotic mechanism of action. Aim 2 identifies the material property characteristics of biodegradable and biocompatible polymeric MPs loaded with either DEX or RLX. Aim 3 evaluates the pharmacokinetics and efficacy of the optimal DEX MP + RLX MP codelivery formulation cocktail identified in Aim 2 using an established in vivo shoulder contracture model.