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.

项目概要/摘要 基于肺泡巨噬细胞群的细胞内感染仍然是最具挑战性的问题之一 抗感染环境和未满足的医疗需求，例如结核病、军团菌病、兔热病和 类鼻疽在全球范围内导致高死亡率和发病率 该项目的长期目标是 开发并验证一种名为“drugamers”的新型可吸入大分子治疗平台，其目标是 抗生素和抗生素药物组合作用于肺泡巨噬细胞，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中尚不存在。 和递送系统，是设计定制药代动力学 (PK) 药物释放曲线的能力 肺泡室和目标肺泡巨噬细胞与特定的 PK 特征相匹配 为了实现这一目标，该项目带来了抗生素类别和特定细菌感染过程。 跨学科团队聚集在一起，涵盖聚合物疗法、肺泡巨噬细胞的聚糖靶向以及 基于肺泡的细菌病理学和治疗的临床专业知识最初的治疗重点是。 兔热病和类鼻疽，拥有临床研究人员并可使用 BSL-3 人类病原体模型和 该提案围绕 4 个具体目标构建：(1) 合成构建甘露糖靶向设施。 氟喹诺酮类药物、β-内酰胺类药物和氨基糖苷类药物的药物异构体以及受控制的药物组合 (2) 优化释放曲线和结构形态，旨在优化肺泡巨噬细胞的摄取。 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 - 基于已知的药物剂量曲线对小鼠模型中的药物库进行分析 根据这些体内特性选择优化的抗生素药物。 进入下一个目标的兔热病和类鼻疽替代模型（3）评估体内杀菌作用。 通过目标 2 中的获胜特性选择的甘露糖靶向药物分子的功效。药物分子 将测试雾化给药治疗高致死性小鼠疾病的能力 (4)通过替代弗朗西斯氏菌和伯霍尔德氏菌的受控雾化感染的高度模型。 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 BSL3 选择剂中的土拉弗朗西斯菌和类鼻疽伯克霍尔德菌 如果成功，该项目将为未来的临床路径确定先导吸入疗法。 由于药物平台是模块化的，因此它也可以是针对兔热病和类鼻疽的开发。 针对其他未满足的细胞内肺部感染治疗需求而开发，其中药物问题日益严重 耐药性迫切需要该平台的定制和组合剂量曲线。

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