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.

项目总结/文摘