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

缺失受体的难题：通过药物受体调节增强功效

• 批准号: 10708018
• 负责人: MARK W. GRINSTAFF
• 金额: $ 65.28万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708018
• 关键词: Acute; Address; Adverse event; Affect; Animals; Articular Range of Motion; Biological Markers; Biological Response Modifier Therapy; CRISPR/Cas technology; Case Study; Cell physiology; Characteristics; Chemosensitization; Chondrocytes; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Collagen; Contracture; Coupled; Cryoelectron Microscopy; Cutaneous; Data; Development; Dexamethasone; Disease; Disease model; Dose; Drug Administration Routes; Drug Delivery Systems; Drug Design; Drug Kinetics; Drug Modulation; Drug Receptors; Drug Targeting; Experimental Designs; Extracellular Matrix Proteins; Fibroblasts; Formulation; G-Protein-Coupled Receptors; Half-Life; Heart failure; Histologic; Hormones; Human; In Vitro; Injections; Intra-Articular Injections; Joints; Kidney; Kinetics; Ligand Binding; Ligands; Lung; Measures; Mechanics; Metalloproteases; Methodology; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Weight; Motivation; Musculoskeletal; Neurology; Oncology; Particle Size; Pathway interactions; Persons; Pharmaceutical Preparations; Polymers; Pregnant Women; Property; Proteins; Receptor Up-Regulation; Recovery; Regulation; Relaxin; Reporting; Role; Safety; Saline; Serum; Shoulder; Signal Pathway; Signal Transduction; Small Interfering RNA; Specificity; Structure; Symptoms; Synovial Fluid; System; Systemic Scleroderma; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; United States; Validation; antifibrotic treatment; biocompatible polymer; biodegradable polymer; canine model; cartilaginous; clinical efficacy; clinical translation; clinically relevant; coronary fibrosis; cost; crystallinity; cytotoxicity; density; design; disease phenotype; experimental study; frontier; improved; improved outcome; in vivo; insight; joint stiffness; knock-down; member; novel; particle; peptide hormone; preclinical efficacy; prevent; programs; rational design; receptor; receptor binding; receptor density; receptor expression; receptor upregulation; skin fibrosis; small molecule; stem; targeted delivery; transcriptome sequencing

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.

项目概要/摘要 该提案概述了先进的药物输送方法，论证了生物治疗的力量，以及 特异性的好处是 靶向生物治疗的固有特征是以基于同源受体的预测疗效为代价的 以足够高的密度存在以达到治疗效果。 能够实现局部和延长的药物释放然而，局部化只是有效药物的一个组成部分。 在这里，我们提出了一种先进的药物输送系统，经过合理设计以增强药物作用。 活性，同时定位和延长生物治疗浓度作为临床相关。 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 RXFP1 均可治疗肩部挛缩的根本原因 RLX 通过上调基质来重塑细胞外基质 (ECM) 蛋白。 我们最近做出了令人兴奋的发现： 地塞米松（DEX）增加纤维化滑膜细胞中RXFP1的表达并进一步探索 RLX和DEX的分子作用机制将增强药物设计的合理性我们将检验这一假设。 通过局部单一关节内 (IA) 共同施用聚合物微粒 (MP) 的 RLX 和 DEX 注射到滑膜间隙，将迅速缓解关节纤维化症状（关节僵硬增加和 此外，DEX RLX 抗纤维化活性的增强将减少最小有效剂量并提高恢复率 调节 RXFP1 受体密度的成功完成将为该疾病提供一种新的治疗方法。 关节纤维化，一种使人衰弱的疾病，影响着美国超过 1500 万人，以及 证明提供生物治疗药物同时增加目标受体密度的重要性 重要的是，重要的初步数据支持所提出的研究，且特征明确。 材料和严格的实验设计已经建立，并且必要的跨学科合作和 该五年提案的具体目标如下。 目标 1 确定 RLX 的配体-受体结合机制以及 TGF-β1 和 DEX 在调节中的新作用 RXFP1 表达以及 RLX 的抗纤维化作用机制 Aim 2 确定了材料特性。 负载 DEX 或 RLX Aim 3 的可生物降解和生物相容性聚合物 MP 的特性。 评估最佳 DEX MP + RLX MP 共递送配方混合物的药代动力学和功效 使用已建立的体内肩部结构模型在目标 2 中确定了这一点。