Thermal Targeting of Antimicrobial Drugs to Sites of Infection

抗菌药物热靶向感染部位

• 批准号: 7481628
• 负责人: Gary Fujii
• 金额: $ 30万
• 依托单位: MOLECULAR EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481628
• 关键词: Amikacin; Anti-Bacterial Agents; Antifungal Agents; Antiviral Agents; Bacteria; Blood; Blood Circulation; Clinical; Colony-forming units; Development; Dose; Drug Formulations; Encapsulated; Engineering; Extravasation; Eye; Goals; Infection; Lipids; Liposomes; Localized; Lung; Membrane; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Procedures; Pseudomonas Infections; Pseudomonas aeruginosa; Public Health; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; Spleen; Stream; Subgroup; Technology; Temperature; Testing; Therapeutic Effect; Time; antimicrobial; antimicrobial drug; clinically relevant; concept; design; experience; follow-up; immunosuppressed; improved; intravenous injection; microbial; mouse model; novel; novel strategies; pathogen; research clinical testing; targeted delivery

DESCRIPTION (provided by applicant): The primary goal of this SBIR AT Phase I proposal is to establish the proof of concept for a new approach to targeted delivery of antimicrobial agents to sites of infection. The studies proposed in this Phase I SBIR AT application will be specifically focused on demonstrating, for the first time, that novel liposome formulations engineered to release their contents at well-defined temperatures can be used to selectively deliver antimicrobial agents to sites of infection. Our central hypothesis is that the delivery of an antimicrobial agent by thermally sensitive liposomes (TSLs) to an infection site, where elevated temperatures are likely to exist, will result in the immediate release of the antimicrobial compound at the infection site thus resulting in an enhanced therapeutic effect. To establish the viability of this approach, we have chosen Pseudomonas aeruginosa as a model pathogen because of its clinical relevance. Our approach is to formulate a model antibacterial drug, such as amikacin, into TSLs and test them in mouse models of Pseudomonas infection. The antibacterial TSL formulations will be compared against free drug and conventional liposome formulations for enhanced efficacy in both splenic and pulmonary Pseudomonas infection models. PUBLIC HEALTH RELEVANCE: To demonstrate the initial proof of concept for the utility of TSLs, we will use an existing passive loading method to encapsulate amikacin into different TSL formulations. The release temperature of the TSLs will be varied in 1-2 degree increments by changing the lipid composition. Each TSL formulation will be tested in a pulmonary mouse model of Pseudomonas aeruginosa infection. In this model, immunosuppressed mice will be challenged intranasally with 100-200 cfu of Pseudomonas aeruginosa and treated with the candidate TSL formulations at different doses. The mice will be monitored for survival and signs of morbidity. The TSL formulations will also be tested in a splenic Pseudomonas aeruginosa infection model. Immunosuppressed mice will be intraperitoneally challenged with 200 cfu of Pseudomonas aeruginosa. In this model, the bacteria first localize in the spleen and then disseminate into the bloodstream. The mice will be monitored for survival and signs of morbidity. Colony forming units will be determined in both the blood and spleen.

描述（由申请人提供）：SBIR AT I期提案的主要目标是建立一种新方法的概念验证，该方法将抗菌剂靶向递送至感染部位。在该I期SBIR AT申请中提出的研究将首次特别集中于证明，经工程设计以在明确定义的温度下释放其内容物的新型脂质体制剂可用于选择性地将抗菌剂递送至感染部位。我们的中心假设是，通过热敏脂质体（TSL）将抗微生物剂递送至可能存在高温的感染部位，将导致抗微生物化合物在感染部位立即释放，从而导致增强的治疗效果。为了建立这种方法的可行性，我们选择铜绿假单胞菌作为模型病原体，因为它的临床相关性。我们的方法是将模型抗菌药物（如阿米卡星）配制成TSL，并在假单胞菌感染的小鼠模型中进行测试。在脾和肺假单胞菌感染模型中，将抗菌TSL制剂与游离药物和常规脂质体制剂进行比较，以增强疗效。公共卫生相关性：为了证明TSL效用的初步概念验证，我们将使用现有的被动加载方法将阿米卡星封装到不同的TSL制剂中。通过改变脂质组成，TSL的释放温度将以1-2度的增量变化。将在铜绿假单胞菌感染的肺部小鼠模型中测试每种TSL制剂。在该模型中，免疫抑制的小鼠将用100-200 cfu的铜绿假单胞菌鼻内攻击，并用不同剂量的候选TSL制剂治疗。将监测小鼠的存活率和发病体征。还将在脾铜绿假单胞菌感染模型中检测TSL制剂。免疫抑制小鼠将用200 cfu铜绿假单胞菌腹腔内激发。在这个模型中，细菌首先定位在脾脏中，然后传播到血液中。将监测小鼠的存活率和发病体征。将测定血液和脾脏中的菌落形成单位。