Development of a Thrombin-Sensitive Recombinant Silk, "Smart" Drug Delivery System

凝血酶敏感的重组丝“智能”给药系统的开发

• 批准号: 9124878
• 负责人: AMANDA BROOKS
• 金额: $ 7.25万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124878
• 关键词: Achievement; Address; American; Antibiotic Resistance; Antibiotic Therapy; Bacteria; Bacterial Antibiotic Resistance; Biomimetics; Biopolymers; Centers for Disease Control and Prevention (U.S.); Development; Drug Delivery Systems; Economic Burden; Encapsulated; Engineering; Exudate; Health; Health Care Costs; Healthcare; Healthcare Systems; Human; In Vitro; Infection; Infection Control; Kinetics; Marketing; Micelles; Multi-Drug Resistance; Nanosphere; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Polymers; Predisposition; Production; Proteins; Pseudomonas aeruginosa; Public Health; Recombinants; Serum; Silk; Staphylococcus aureus; Testing; Therapeutic; Thrombin; Tobramycin; Vesicle; World Health Organization; antimicrobial; antimicrobial drug; base; clinical practice; combat; copolymer; cost; drug discovery; in vivo; killings; nanocapsule; nanoscale; novel strategies

 DESCRIPTION (provided by applicant): The rise in antibiotic resistant bacterial strains is quickly outpacing drug discovery, imposing an enormous economic burden on the world's healthcare systems with estimates reaching $20 billion in direct healthcare costs. Listed by the World Health Organization as one of the top 3 threats to global public health, more than 2 million Americans suffer from an antibiotic-resistant infection with over 23,000 succumbing annually (according to the Centers for Disease Control, USA). Combating multidrug resistance necessitates a paradigm shift away from exclusive drug discovery efforts toward "smart", infection-responsive drug delivery systems for current therapeutics. These observations culminate in the following global hypothesis: a bioinspired copolymer containing a thrombin-sensitive linker chemically grafted to a biomimetic recombinant silk peptide will provide a self-assembling nanocapsule drug delivery vehicle that will only release its drug payload in the presence of up-regulated thrombin-like activity associated specifically with S. aureus and P. aeruginosa infections. To address this hypothesis, fabrication, analysis and testing of this new smart drug delivery system will be pursued via the following specific aims: 1) Chemically graft a thrombin-responsive peptide to a recombinant silk peptide; 2) Determine the proteolytic stability of the newly created thrombin sensitive silk-based biomimetic polymer to S. aureus and P. aeruginosa thrombin-like activity; 2) Assess the size, polydispersity, and tobramycin encapsulation efficacy of thrombin-sensitive silk biopolymer nanoscale micelles. Achievement of these aims will yield a new infection responsive drug delivery system that will only release its drug payload in the presence of up-regulated thrombin activity. Everything is currently in place to successfully execute these aims and provide a powerful platform to proceed to more extensive in vivo testing, ultimately, controlling the rising tide of multidrug resistant S. aureus and P. aeruginosa infections.

 描述（由申请人提供）：抗生素耐药菌株的增加迅速超过药物发现，给世界医疗保健系统带来巨大的经济负担，估计直接医疗保健成本达到200亿美元。世界卫生组织将其列为全球公共卫生的三大威胁之一，超过200万美国人患有耐药性感染，每年有超过23，000人死亡（根据美国疾病控制中心）。对抗多药耐药性需要一个范式的转变，从排他性的药物发现努力转向“智能”，感染反应的药物输送系统，目前的治疗。这些观察结果最终导致了以下总体假设：含有凝血酶敏感性接头的生物启发共聚物化学接枝到仿生重组丝肽将提供自组装纳米胶囊药物递送载体，其仅在存在与S特异性相关的上调凝血酶样活性的情况下释放其药物有效载荷。金黄色葡萄球菌和铜绿假单胞菌感染。为了解决这一假设，将通过以下具体目标来实现这种新型智能药物递送系统的制造、分析和测试：1）将凝血酶响应性肽化学接枝到重组丝肽; 2）测定新创建的凝血酶敏感的丝基仿生聚合物对S.金黄色葡萄球菌和铜绿假单胞菌凝血酶样活性; 2）评估凝血酶敏感性丝生物聚合物纳米级胶束的尺寸、多分散性和妥布霉素包封功效。这些目标的实现将产生一种新的感染响应性药物递送系统，其仅在存在上调的凝血酶活性的情况下释放其药物有效载荷。目前一切都已就绪，可以成功实现这些目标，并提供一个强大的平台，进行更广泛的体内试验，最终控制多药耐药S。金黄色 和铜绿假单胞菌感染。