Collaborative Research: Polymeric Drug Delivery Systems and Biofilms in the Lung

描述(申请人提供)：生物膜是一种微生物群落，可以在植入的医疗设备上形成，导致危及生命的感染。在包括囊性纤维化(CF)在内的慢性肺部感染患者的肺中也发现了生物膜，这是该患者群体中发病率和死亡率的主要原因。许多生物膜的组成微生物对抗菌剂表现出抗药性，这使得此类感染的医疗治疗变得复杂。因此，尽管常规的抗生素治疗，微生物仍以生物膜生长模式持续存在，对许多患者群体构成了重大的健康威胁。 这项提议的基本目标是开发一种安全有效的药物输送系统，以杀灭生长在呼吸道生物膜中的细菌。拟议的给药系统基于雾化，这是一种将治疗剂雾化并通过吸入传递到呼吸道的过程。治疗策略是基于银基抗菌化合物，特别是银卡宾络合物(SCCs)。其他潜在的治疗剂包括银外流抑制剂、反群体感应药物和降解细胞外聚合物(EPS)或生物膜结构成分的酶。 这项拟议的研究将探索在水溶液中以及在可生物降解的聚合物纳米球中传递这些试剂的有效性。以可溶形式输送到生物膜中的试剂通过生物膜表面进入生物膜。另一方面，纳米球穿过生物膜的裂缝和毛孔，然后随着时间的推移溶解并缓慢释放治疗剂。一个由工程师、化学家、生物学家、应用数学家和一名医学博士组成的跨学科团队将进行这项拟议的研究。该团队成员将合成作为候选抗菌剂的新型卡宾银络合物，制造包含银基络合物和其他试剂的可生物降解的聚合物纳米球，进行体外和体内实验，以确定各种化合物和递送系统对铜绿假单胞菌、耐甲氧西林金黄色葡萄球菌(MRSA)和炭疽菌生物膜的治疗效果，并开发全面的数学模型，作为发现有效治疗策略的预测工具。

DESCRIPTION (provided by applicant): A biofilm is a community of microorganisms that can form on implanted medical devices leading to life threatening infections. Biofilms are also found within the lungs of patients with chronic pulmonary infections including patients with cystic fibrosis (CF) and are the major cause of morbidity and mortality in this patient population. The medical treatment of such infections is complicated by the fact that the constituent microorganisms of many biofilms display resistance to antimicrobial agents. Consequently, the persistence of microorganisms in biofilm growth mode, despite conventional antibiotic therapy, poses significant health threats to numerous patient populations. The basic goal of this proposal is to develop a safe and effective drug delivery system to kill bacteria growing in biofilms in the respiratory tract. The proposed delivery system is based upon nebulization, the process of aerosolizing therapeutic agents for delivery by inhalation to the respiratory tract. The treatment strategy is based upon silver-based antimicrobial compounds, in particular, silver carbene complexes (SCCs). Other potential therapeutic agents include silver-efflux inhibitors, anti-quorum sensing drugs, and enzymes that degrade the extracellular polymeric substances (EPS), or structural components of the biofilm. The proposed research will explore the efficacy of delivering these agents both in an aqueous solution, as well as in biodegradable polymer nanospheres. Agents delivered to the biofilm in soluble form enter the biofilm through its surface. The nanospheres, on the other hand, penetrate the biofilm through its cracks and pores, and then dissolve and slowly release the therapeutic agents over time. An interdisciplinary team of engineers, chemists, biologists, applied mathematicians, and a medical doctor will conduct the proposed research. Members of this team will synthesize novel silver carbene complexes as candidate antimicrobial agents, fabricate biodegradable polymeric nanospheres that contain silver-based complexes and other agents, perform in vitro and in vivo experiments to determine the efficacy of various compounds and delivery systems for treating biofilms of Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus (MRSA), and anthrax, and develop comprehensive mathematical models as a predictive tool for discovering effective treatment strategies.