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

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许多类型疾病治疗的主要挑战。有效的口服剂量在特定组织内达到高浓度，同时尽量减少全身毒性仍然是一个重大挑战。此外，传统的聚合物给药系统，如植入物、可注射微球和贴片，每年有数千万人使用，但往往产生不理想的药物释放谱。我们的目标是开发一种自主药物输送系统，根据生物刺激滴定药物释放量，确保药物仅在需要时以治疗相关浓度释放。与布里格姆妇女医院的风湿病学家Tony Aliprantis博士合作，我们的目标是在炎症性关节炎模型中展示该技术的体外和体内概念验证。仅在美国，估计就有250万人

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.