A Drug Delivery Platform For Near-Term Treatment of Proteolytic Disease

用于近期治疗蛋白水解疾病的药物输送平台

• 批准号: 8725794
• 负责人: Jeffrey Michael Karp
• 金额: $ 20万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725794
• 关键词: 3-Dimensional; Address; Adrenal Cortex Hormones; Adverse effects; Architecture; Arthritis; Biological; Biological Markers; Cardiovascular Diseases; Chronic; Collaborations; Connective Tissue; Cost Measures; Defect; Degenerative polyarthritis; Diffusion; Disease; Disease remission; Dose; Drug Delivery Systems; Ensure; Environmental Risk Factor; Enzymes; Flare; Fluid Shifts; Gastrointestinal Diseases; Gel; Generations; Goals; Hepatic; Hospitalization; Hospitals; Hydrogels; Immune system; Implant; In Vitro; Inflammation; Inflammatory; Injectable; Joints; Literature; Malignant Neoplasms; Matrix Metalloproteinases; Methods; Microspheres; Modeling; Mouth Diseases; Oral; Oral Administration; Organ Culture Techniques; Patients; Pharmaceutical Preparations; Physiology; Preparation; Process; Prodrugs; Publishing; Rheumatoid Arthritis; Rodent Model; Severity of illness; Stimulus; Stomach; Symptoms; Synovial Fluid; System; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Woman; Work; Wound Healing; absorption; arthropathies; base; crosslink; design; enzyme pathway; extracellular; in vivo; in vivo Model; intestinal epithelium; nanoscale; non-compliance; novel; response; rheumatologist; uptake

DESCRIPTION (provided by applicant): Delivering drugs to patients in a safe, effective, and compliant manner is a major challenge for treatment of many types of disease. Effective oral dosing to achieve high concentrations of drugs within specific tissues while minimizing systemic toxicity remains a significant challenge. Additionally, conventional polymeric drug delivery systems such as implants, injectable microspheres, and patches are used by tens of millions of people annually, yet often produce sub-optimal drug release profiles. We aim to develop an autonomous drug delivery system that titrates the amount of drug released in response to a biological stimulus, ensuring the drug is released only when needed at a therapeutically relevant concentration. In collaboration with Dr. Tony Aliprantis, a Rheumatologist at the Brigham and Women's hospital, we aim to demonstrate an in vitro and in vivo proof of concept for this technology in models of inflammatory arthritis. In the U.S. alone, it is estimated that 2.5 million people suffer from rheumatoid arthritis with a monetary cost measured in the billions. This work will assess the hypothesis that drug based hydrogels, containing enzyme labile linkers, that are tailored to disassemble in response to enzymes expressed during exacerbations from inflammatory arthritis can serve as an effective on demand approach for local long term drug delivery to treat inflammatory joint disease. These gels will be tested using a novel in vitro 3-dimensional synovial micromass organ culture method that faithfully replicates many aspects of the synovial lining physiology and architecture. The gels will also be tested in the rodent model of inflammatory arthritis. This application will focus on addressing the following aims: Aim 1: a) Synthesize prodrug-based hydrogels that disassemble in response to MMPs those are upregulated within joints in IA and b) confirm capacity for IA synovial fluid to disassemble prodrug hydrogels in an MMP specific manner. Aim 2: Confirm MMP selectivity and 'on demand' disassembly in synovial micromass organ culture. Aim 3: a) Demonstrate on demand disassembly of MMP specific prodrug hydrogels in vivo and b) Demonstrate capacity for prodrug based hydrogels to ameliorate inflammatory arthritis In vivo.

描述（由申请人提供）：以安全、有效和合规的方式向患者提供药物是治疗多种疾病的主要挑战。有效口服给药以在特定组织内实现高浓度药物，同时最大限度地减少全身毒性仍然是一个重大挑战。此外，传统的聚合物药物递送系统（例如植入物、可注射微球和贴片）每年被数千万人使用，但通常会产生次优的药物释放曲线。我们的目标是开发一种自主药物输送系统，该系统可以滴定响应生物刺激而释放的药物量，确保药物仅在需要时以治疗相关浓度释放。我们与布莱根妇女医院的风湿病学家 Tony Aliprantis 博士合作，旨在在炎症性关节炎模型中展示该技术的体外和体内概念证明。仅在美国，估计就有 250 万 人们患有类风湿性关节炎，造成的经济损失高达数十亿美元。这项工作将评估以下假设：基于药物的水凝胶含有酶不稳定的连接体，专门针对炎症性关节炎恶化期间表达的酶进行分解，可以作为局部长期药物递送治疗炎症性关节疾病的有效按需方法。这些凝胶将使用新型体外 3 维滑膜微团器官培养方法进行测试，该方法忠实地复制滑膜内层生理学和结构的许多方面。这些凝胶还将在炎症性关节炎的啮齿动物模型中进行测试。本申请将重点关注以下目标：目标 1：a) 合成基于前药的水凝胶，该水凝胶可响应 IA 关节内上调的 MMP 进行分解，b) 确认 IA 滑液以 MMP 特定方式分解前药水凝胶的能力。目标 2：确认滑膜微团器官培养中的 MMP 选择性和“按需”拆卸。目标 3：a) 展示 MMP 特异性前药水凝胶在体内的按需分解，b) 展示基于前药的水凝胶改善体内炎症性关节炎的能力。