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

描述（由申请人提供）：生物膜是一种微生物群落，可在植入的医疗器械上形成，导致危及生命的感染。生物膜也存在于慢性肺部感染患者（包括囊性纤维化（CF）患者）的肺部，是该患者人群发病率和死亡率的主要原因。这种感染的医学治疗由于许多生物膜的组成微生物显示出对抗微生物剂的抗性的事实而变得复杂。因此，尽管有常规抗生素治疗，但微生物在生物膜生长模式中的持续存在对许多患者群体构成显著的健康威胁。 该提案的基本目标是开发一种安全有效的药物递送系统，以杀死呼吸道生物膜中生长的细菌。所提出的递送系统基于雾化，雾化治疗剂以通过吸入递送至呼吸道的过程。治疗策略基于银基抗微生物化合物，特别是银卡宾络合物（SCC）。其他潜在的治疗剂包括银外排抑制剂、抗群体感应药物和降解细胞外聚合物（EPS）或生物膜的结构组分的酶。 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递送这些药剂的功效。以可溶形式递送至生物膜的试剂通过其表面进入生物膜。另一方面，纳米球通过其裂缝和孔隙渗透生物膜，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生组成的跨学科团队将进行拟议的研究。该团队的成员将合成新型银卡宾络合物作为候选抗菌剂，制造含有基于银的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用于治疗铜绿假单胞菌、耐甲氧西林金黄色葡萄球菌（MRSA）和炭疽的生物膜的功效，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.