Engineered Antimicrobial Platform to Target Pulmonary Intracellular Infections

针对肺部细胞内感染的工程抗菌平台

• 批准号: 10287484
• 负责人: Daniel M. Ratner
• 金额: $ 63.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-13 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287484
• 关键词: Aerosols; Alveolar; Alveolar Macrophages; Aminoglycoside Antibiotics; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Architecture; Area; Bacteria; Bacterial Infections; Biodistribution; Biological Availability; Blood; Burkholderia pseudomallei; Carbapenems; Chlamydophila Infections; Ciprofloxacin; Clinical; Clinical Investigator; Clinical Pathways; Clinical Trials; Combined Antibiotics; Custom; Development; Disease; Disease model; Dose; Drug Combinations; Drug Kinetics; Drug resistance; Engineering; Enzymes; Evaluation; Exhibits; Family; Fluoroquinolones; Formulation; Francisella; Francisella tularensis; Future; Goals; Histologic; Individual; Infection; Inhalation; Intravenous; Lead; Legionellosis; Libraries; Lung; Lung infections; Mannose; Measures; Medical; Melioidosis; Minimum Inhibitory Concentration measurement; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Mycobacterium Infections; Oral Administration; Organ; Pathology; Patient-Focused Outcomes; Pharmaceutical Preparations; Pneumonia; Polymer Chemistry; Polymers; Polysaccharides; Population; Process; Prodrugs; Production; Property; Public Health; Pulmonary tularemia; Q Fever; Reporting; Route; Safety; Schedule; Site; Structure; System; Testing; Therapeutic; Time; Toxic effect; Tuberculosis; Tularemia; Universities; Upper Respiratory Infections; Washington; aerosolized; analytical method; antimicrobial; bactericide; base; beta-Lactams; biomaterial compatibility; biosafety level 3 facility; biothreat; clinical development; combat; controlled release; cost; design; drug release profile; experimental study; global health; human pathogen; in vivo; liquid chromatography mass spectrometry; lung basal segment; lung pathogen; macrophage; monomer; mortality; mouse model; multidisciplinary; nanoparticle; non-tuberculosis mycobacteria; novel strategies; novel therapeutics; polymerization; synthetic construct; translation to humans; uptake

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.

项目摘要/摘要 基于肺肺泡巨噬细胞种群中的细胞内感染仍然是最挑战的之一 反感染设置和未满足的医疗需求。诸如结核病，遗传病，tularemia和 Melioidosis在全球范围内导致高死亡率和发病率成本。该项目的长期目标是 开发和验证一个被称为“药物”的新的可吸入的大分子治疗平台，该平台的目标 肺泡巨噬细胞的抗生素和抗生素组合，以更好地治疗基于肺部的细胞内 感染。该平台的关键新属性，目前尚不存在于临床上的治疗中 和输送系统，是设计定制量身定制的药代动力学（PK）药物释放概况的能力 牙槽室和靶向肺泡巨噬细胞，与所需的PK轮廓相匹配 抗生素类和特定细菌感染过程。为了实现这一目标，该项目带来了 跨聚合物疗法，聚糖靶向肺泡巨噬细胞和一个多学科团队 基于肺泡的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 Tularemia和Melioidoiss，临床研究人员，并使用BSL-3人类病原体模型和 设施。该提案的结构围绕4个特定目的：（1）合成构建甘露糖的目标 氟喹诺酮，β-内酰胺和氨基糖苷药物和药物组合的药物 旨在优化肺泡巨噬细胞吸收的释放曲线和建筑形态。 （2）优化 生物相容性，肺泡巨噬细胞靶向和PK特性 - 通过液相色谱测量 - 质谱分析 - 基于已知药物剂量特征的鼠模型中药物库的质谱分析 这些主要类别的抗生素类。根据这些体内特性选择优化的药物以携带 （3）评估体内杆菌 通过在AIM 2中选择的甘露糖靶向药物的效率。 通过雾化给药将测试其在高致命小鼠疾病中固化的能力 替代弗朗西斯氏菌和荷兰细菌受控的雾化感染的模型。 （4）高度 在AIM 3中选择的有效药物器设计将在人类病原体小鼠模型中评估 华盛顿大学BSL3 Select Agent 设施。如果成功，该项目将确定未来临床途径的铅遗传疗法 针对tularemia和Melioidisois的发育。因为吸毒者平台是模块化的，所以也可能是 针对其他未满足的细胞内感染疗法需求开发的，在越来越多的药物问题 电阻为该平台的量身定制和组合剂量配置文件提供了迫切的需求。

项目成果

A macrophage-targeted platform for extending drug dosing with polymer prodrugs for pulmonary infection prophylaxis.

• DOI: 10.1016/j.jconrel.2020.11.031
• 发表时间: 2021-02-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Chavas TEJ;Su FY;Srinivasan S;Roy D;Lee B;Lovelace-Macon L;Rerolle GF;Limqueco E;Skerrett SJ;Ratner DM;West TE;Stayton PS
• 通讯作者: Stayton PS

Well-Defined Mannosylated Polymer for Peptide Vaccine Delivery with Enhanced Antitumor Immunity.

• DOI: 10.1002/adhm.202101651
• 发表时间: 2022-05
• 期刊: ADVANCED HEALTHCARE MATERIALS
• 影响因子: 10
• 作者: Lv, Shixian;Song, Kefan;Yen, Albert;Peeler, David J.;Nguyen, Dinh Chuong;Olshefsky, Audrey;Sylvestre, Meilyn;Srinivasan, Selvi;Stayton, Patrick S.;Pun, Suzie H.
• 通讯作者: Pun, Suzie H.

Polymer-augmented liposomes enhancing antibiotic delivery against intracellular infections.

• DOI: 10.1039/c8bm00282g
• 发表时间: 2018-06-25
• 期刊: Biomaterials science
• 影响因子: 6.6
• 作者: Su FY ;Chen J ;Son HN ;Kelly AM ;Convertine AJ ;West TE ;Skerrett SJ ;Ratner DM ;Stayton PS
• 通讯作者: Stayton PS

Macrophage-targeted drugamers with enzyme-cleavable linkers deliver high intracellular drug dosing and sustained drug pharmacokinetics against alveolar pulmonary infections.

• DOI: 10.1016/j.jconrel.2018.08.014
• 发表时间: 2018-10-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Su FY;Srinivasan S;Lee B;Chen J;Convertine AJ;West TE;Ratner DM;Skerrett SJ;Stayton PS
• 通讯作者: Stayton PS