Thermal Targeting of Antimicrobial Drugs to Sites of Infection

描述（由申请人提供）：这个SBIR AT I期提案的主要目标是建立一种新的方法的概念证明，这种方法可以将抗菌剂靶向递送到感染部位。这项I期SBIR AT申请的研究将首次特别关注于证明新型脂质体配方可以在规定的温度下释放其内容物，可用于选择性地将抗菌药物输送到感染部位。我们的中心假设是，通过热敏脂质体（TSLs）将抗菌药物递送到可能存在高温的感染部位，将导致抗菌化合物在感染部位立即释放，从而增强治疗效果。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TSLs，并在假单胞菌感染的小鼠模型中进行测试。抗菌TSL制剂将与游离药物和传统脂质体制剂进行比较，以增强脾和肺假单胞菌感染模型的疗效。公共卫生相关性：为了证明TSL效用的初步概念证明，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配方中。通过改变脂质组成，tsl的释放温度会以1-2度的增量变化。每种TSL制剂将在铜绿假单胞菌感染的肺小鼠模型中进行测试。在该模型中，免疫抑制小鼠将被100-200 cfu铜绿假单胞菌鼻内攻击，并以不同剂量的候选TSL制剂治疗。将监测小鼠的生存和发病迹象。TSL制剂也将在脾脏铜绿假单胞菌感染模型中进行测试。免疫抑制小鼠腹腔注射200 cfu铜绿假单胞菌。在这个模型中，细菌首先在脾脏中定位，然后扩散到血液中。将监测小鼠的生存和发病迹象。菌落形成单位将在血液和脾脏中确定。

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.