Nanomedicine for ARDS: A new paradigm to target drugs to multiple cell types within alveolar capillaries

ARDS 纳米医学：将药物靶向肺泡毛细血管内多种细胞类型的新范例

• 批准号: 10678910
• 负责人: Jacob Brenner
• 金额: $ 40.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678910
• 关键词: Acute; Acute Respiratory Distress Syndrome; Air Sacs; Alveolar; Alveolar Cell; Alveolus; American; Antibodies; Binding; Biology; Blood; Blood capillaries; Cannulations; Cells; Clinical Trials; Combined Modality Therapy; Dose; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Modulation; Drug Side Effects; Drug Targeting; Drug toxicity; Endothelial Cells; Endothelium; Failure; Functional disorder; Goals; Human; Imatinib; Impairment; Inhalation; Label; Left; Lipids; Liposomes; Liquid substance; Lung; Measures; Mediating; Mediator; Methods; Modeling; Mus; Nanotechnology; Nebulizer; Organ failure; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Publications; Publishing; Pulmonary Artery Branch; Role; Signal Pathway; Structure of parenchyma of lung; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Time; Tissue Banks; Toxic effect; Transplantation; Treatment Efficacy; Work; body system; cell type; design; human model; improved; in vivo; inflammatory lung disease; invention; mouse model; nanocarrier; nanomedicine; nanometer; neutrophil; neutrophil elastase inhibitor; novel; novel therapeutics; pharmacokinetic model; pharmacologic; prevent; response; screening; side effect; small molecule; synergism; theories; tool; treatment optimization; uptake

ABSTRACT Dozens of drugs have failed in clinical trials for the inflammatory lung disease ARDS (acute respiratory distress syndrome), largely due to 3 pharmacological challenges particular to ARDS: ARDS patients have multi-system organ failure, so cannot tolerate off-target drug side effects; the column of liquid covering alveoli prevents effective inhaled delivery; dozens of signaling pathways underlie ARDS, so modulating just one will not work. To overcome these 3 challenges, we designed M-LACs, which are 100-nanometer lipid spheres (liposomes), loaded with multiple drugs, and coated with targeting tags that cause them to massively accumulate in the capillaries of the alveoli (air sacs of the lungs). We have previously published on the benefits of M-LACs targeted to alveolar endothelial cells, but have long seen the need to target the other major alveolar capillary cell type, alveolar marginated neutrophils. Here we introduce new targeting tags that can massively concentrate M-LACs in alveolar neutrophils. With the new ability to target LACs to both endothelium and neutrophils, we can now answer fundamental questions in ARDS biology (Aim 1) and general pharmacology (Aim 2), while radically improving M-LACs as a therapy for ARDS (Aim 3). Aim 1: In ​ex vivo​ human lungs and ​in vivo mouse models of ARDS, we quantify the relative number of marginated neutrophils compared to naive cases, and we will measure how well neutrophils and endothelial take up M-LACs. Aim 2: We will test the “depot theory” of targeted drug delivery, which says drugs efficiently elute from targeted cells to their neighbors. We will test whether drugs meant to act in neutrophils (e.g., neutrophil elastase inhibitors) will ameliorate ARDS-like phenotypes the same or worse if targeted to endothelial cells, and vice versa. Aim 3: We will identify the principles of combination therapy. We hypothesize that the most efficacious combinations will be a pair of neutrophil- and endothelial-modulating drugs (e.g., as opposed to 2 endothelial-modulating drugs). By the end of these studies, we will have uncovered new ARDS biology and answered fundamental questions in pharmacology. Additionally, we will have created a highly optimized therapy for ARDS that we will have tested in multiple mouse models of ARDS and in human lungs.

摘要 数十种药物在治疗炎症性肺病ARDS(急性)的临床试验中失败 呼吸窘迫综合征)，主要是由于ARDS特有的3个药理学挑战：ARDS 患者有多系统器官衰竭，不能容忍非靶向药物的副作用；专栏 覆盖肺泡的液体阻止了有效的吸入给药；ARDS背后的数十个信号通路， 因此，只调节一个是行不通的。为了克服这三个挑战，我们设计了M-Lacs，它 是100纳米的脂球(脂质体)，装载了多种药物，并覆盖了靶向 导致它们大量聚集在肺泡(肺的气囊)的毛细血管内的标签。 我们之前已经发表了针对肺泡内皮细胞的M-Lacs的好处，但 长期以来认为需要瞄准另一种主要的肺泡毛细血管细胞类型，即肺泡边缘形成 中性粒细胞。在这里，我们引入了新的靶向标记，可以在肺泡内大量浓缩M-Lacs 中性粒细胞。随着针对内皮和中性粒细胞的Lacs的新能力的出现，我们现在可以 回答ARDS生物学(目标1)和普通药理学(目标2)的基本问题，同时 从根本上改进M-Lacs作为ARDS的治疗方法(目标3)。目的1：在​体外​人肺和体内​ 在ARDS小鼠模型中，我们量化了与单纯中性粒细胞相比的边缘中性粒细胞的相对数量 我们将测量中性粒细胞和内皮细胞摄取M-Lacs的情况。目标2：我们将测试 靶向药物输送的“仓库理论”认为，药物有效地从靶细胞洗脱到 他们的邻居。我们将测试旨在作用于中性粒细胞的药物(例如，中性粒细胞弹性蛋白酶 抑制剂)将改善ARDS样表型，如果针对内皮细胞，则相同或更差，以及 反之亦然。目标3：我们将确定联合治疗的原则。我们假设大多数人 有效的组合将是一对中性粒细胞和内皮调节药物(例如，AS 而不是2种内皮调节药物)。到这些研究结束时，我们将发现新的 并回答了药理学中的基本问题。此外，我们将有 为ARDS创造了一种高度优化的疗法，我们将在多个小鼠模型上进行测试 ARDS和人的肺中。

项目成果

The Nano-War Against Complement Proteins.

• DOI: 10.1208/s12248-021-00630-9
• 发表时间: 2021-09-10
• 期刊: The AAPS journal
• 作者: Wang Z;Brenner JS
• 通讯作者: Brenner JS

Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE).

• DOI: 10.1016/j.jconrel.2021.12.027
• 发表时间: 2022-04
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Parhiz H;Brenner JS;Patel PN;Papp TE;Shahnawaz H;Li Q;Shi R;Zamora ME;Yadegari A;Marcos-Contreras OA;Natesan A;Pardi N;Shuvaev VV;Kiseleva R;Myerson JW;Uhler T;Riley RS;Han X;Mitchell MJ;Lam K;Heyes J;Weissman D;Muzykantov VR
• 通讯作者: Muzykantov VR

Nanoparticle-Induced Augmentation of Neutrophils' Phagocytosis of Bacteria.

• DOI: 10.3389/fphar.2022.923814
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Rubey, Kathryn M.;Mukhitov, Alexander R.;Nong, Jia;Wu, Jichuan;Krymskaya, Vera P.;Myerson, Jacob W.;Worthen, G. Scott;Brenner, Jacob S.
• 通讯作者: Brenner, Jacob S.

Meta-Analysis of Material Properties Influencing Nanoparticle Plasma Pharmacokinetics.

• DOI: 10.1016/j.ijpharm.2023.122951
• 发表时间: 2023-04
• 期刊: International journal of pharmaceutics
• 影响因子: 5.8
• 作者: Briana Macedo;Manthan Patel;Michael H. Zaleski;Parth Mody;Xiaonan Ma;Patrick Mei;J. Myerson;J. Brenner;P. Glassman

COVID-19 and the Early-Career Physician-Scientist. Fostering Resilience beyond the Pandemic.

• DOI: 10.34197/ats-scholar.2020-0104ps
• 发表时间: 2020-10-23
• 期刊: ATS scholar
• 影响因子: 1.9
• 作者: Kliment CR;Barbash IJ;Brenner JS;Chandra D;Courtright K;Gauthier MC;Robinson KM;Scheunemann LP;Shah FA;Christie JD;Morris A
• 通讯作者: Morris A