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，可以在植入的医疗器械上形成，导致危及生命的感染。在包括囊性纤维化（CF）患者在内的慢性肺部感染患者的肺内也发现了生物膜，这是这类患者发病率和死亡率的主要原因。由于许多生物膜的组成微生物对抗菌剂表现出耐药性，这种感染的医学治疗变得复杂。因此，尽管传统的抗生素治疗，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了重大的健康威胁。

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.