Engineered Antimicrobial Platform to Target Pulmonary Intracellular Infections

项目总结/摘要 基于肺泡巨噬细胞群体的细胞内感染仍然是最具挑战性的疾病之一 抗感染设置和未满足的医疗需求。结核病、军团病、土拉菌病和 类鼻疽病在地球仪中引起高死亡率和发病成本。该项目的长期目标是 开发并验证一种新的可吸入大分子治疗平台，称为“drugamers”， 抗生素和抗生素药物组合到肺泡巨噬细胞，以更好地治疗肺细胞内 感染.该平台的一个关键新特性，目前在临床可用的治疗方法中不存在 和递送系统，是能够设计定制的药代动力学（PK）药物释放曲线， 肺泡隔室和靶向肺泡巨噬细胞与特定的 抗生素类别和特定细菌感染过程。为了实现这一目标，该项目 一个跨聚合物治疗、肺泡巨噬细胞聚糖靶向和 肺泡细菌病理学和治疗方面的临床专业知识。最初的治疗重点是 土拉菌病和类鼻疽，与临床研究人员和获得BSL-3人类病原体模型， 设施该提案围绕4个具体目标构建：（1）合成构建甘露糖靶向 氟喹诺酮类、β-内酰胺类和氨基糖苷类药物的药物使用者以及药物组合， 释放曲线和结构形态设计，以优化肺泡巨噬细胞摄取。(2)优化 生物相容性、肺泡巨噬细胞靶向和PK特性-通过液相色谱法测量- 质谱分析-基于已知的药物给药谱的鼠模型中的drugamer文库 这些主要的抗生素种类。根据这些体内特性选择优化的druggamers携带 进入下一个目标的兔热病和类鼻疽的替代模型。(3)评价体内杀菌性 通过目标2中的获胜属性选择的以甘露糖为目标的druggamers的功效。Drugamers 将测试它们在高致命性小鼠疾病中实现治愈的能力 通过替代弗朗西斯菌和伯霍尔德菌的受控雾化感染的模型。(4)高度 目标3中选择的有效药物设计将在人类病原体小鼠模型中进行评估， 华盛顿大学的土拉热弗朗西斯菌和类鼻疽伯克霍尔德菌BSL 3选择性病原体 设施。如果成功，该项目将为未来的临床路径确定铅吸入疗法 抗兔热病和类鼻疽的发展。由于drugamer平台是模块化的，它也可以是 针对其他未得到满足的细胞内肺部感染治疗需求而开发，其中药物治疗的日益增长的问题 阻力提供了对该平台的定制和组合剂量分布的迫切需要。

PROJECT SUMMARY/ABSTRACT Intracellular infections based in the lung alveolar macrophage population remain one of the most challenging anti-infective settings and unmet medical needs. Diseases such as tuberculosis, legionellosis, tularemia and melioidosis cause high mortality and morbidity costs around the globe. The long-term goal of this project is to develop and validate a new inhalable macromolecular therapeutic platform termed “drugamers” that targets antibiotics and antibiotic drug combinations to the alveolar macrophage to better treat lung-based intracellular infections. A key new property of this platform, that currently does not exist in clinically available therapeutics and delivery systems, is the ability to engineer custom tailored pharmacokinetic (PK) drug release profiles in the alveolar compartment and targeted alveolar macrophages that match the required PK profiles of specific antibiotic classes and specific bacterial infection processes. To achieve this objective, the project brings together a multi-disciplinary team across polymer therapeutics, glycan targeting of alveolar macrophages, and clinical expertise in alveolar-based bacterial pathology and treatment. The initial therapeutic focus is on tularemia and melioidosis, with clinical investigators and access to BSL-3 human pathogen models and facilities. The proposal is structured around 4 specific aims to: (1) Synthetically construct mannose-targeted drugamers of fluoroquinolone, β-lactam, and aminoglycoside drugs and drug combinations with controlled release profiles and architectural morphologies designed to optimize alveolar macrophage uptake. (2) Optimize the biocompatibility, alveolar macrophage targeting, and PK properties - measured by liquid chromatography – mass spectrometry analysis - of the drugamer library in murine models based on known drug dosing profiles of these major classes of antibiotics. Select optimized drugamers based on these in vivo properties to carry forward into the surrogate models of tularemia and melioidosis of the next aim. (3) Evaluate in vivo bactericidal efficacy of the mannose-targeted drugamers selected through their winning properties in Aim 2. Drugamers administered by aerosoloization will be tested for their ability to achieve cures in highly lethal mouse disease models infected by controlled aerosolization of surrogate Francisella and Burholderia bacteria. (4) Highly effective drugamer designs selected in Aim 3 will be assessed in human pathogen mouse models using Francisella tularensis and Burkholderia pseudomallei at the University of Washington BSL3 select agent facility. If successful, this project will identify lead inhalation therapeutics for future clinical pathway development against tularemia and melioidosis. Because the drugamer platform is modular, it could also be developed against other unmet intracellular lung infection therapy needs, where the growing issue of drug resistance provides a compelling need for the tailored and combination dosing profiles of this platform.