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
基本信息
- 批准号:10678910
- 负责人:
- 金额:$ 40.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAcute Respiratory Distress SyndromeAir SacsAlveolarAlveolar CellAlveolusAmericanAntibodiesBindingBiologyBloodBlood capillariesCannulationsCellsClinical TrialsCombined Modality TherapyDoseDrug CarriersDrug CombinationsDrug Delivery SystemsDrug ModulationDrug Side EffectsDrug TargetingDrug toxicityEndothelial CellsEndotheliumFailureFunctional disorderGoalsHumanImatinibImpairmentInhalationLabelLeftLipidsLiposomesLiquid substanceLungMeasuresMediatingMediatorMethodsModelingMusNanotechnologyNebulizerOrgan failurePathway interactionsPatientsPharmaceutical PreparationsPharmacologyPharmacotherapyPhenotypePublicationsPublishingPulmonary Artery BranchRoleSignal PathwayStructure of parenchyma of lungTestingTherapeuticTherapeutic EffectTherapeutic IndexTimeTissue BanksToxic effectTransplantationTreatment EfficacyWorkbody systemcell typedesignhuman modelimprovedin vivoinflammatory lung diseaseinventionmouse modelnanocarriernanomedicinenanometerneutrophilneutrophil elastase inhibitornovelnovel therapeuticspharmacokinetic modelpharmacologicpreventresponsescreeningside effectsmall moleculesynergismtheoriestooltreatment optimizationuptake
项目摘要
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(急性呼吸窘迫综合征)的临床试验中失败
呼吸窘迫综合征),主要是由于3个药理学挑战,特别是ARDS:
患者有多系统器官衰竭,不能耐受脱靶药物副作用;
覆盖肺泡的液体阻止了有效的吸入递送;几十种信号传导途径是ARDS的基础,
因此仅调制一个将不起作用。为了克服这3个挑战,我们设计了M-LAC,
是100纳米的脂质球(脂质体),载有多种药物,并涂有靶向
这些标签导致它们大量积聚在肺泡(肺的气囊)的毛细血管中。
我们之前已经发表了针对肺泡内皮细胞的M-LACs的益处,但
长期以来一直认为需要靶向其他主要肺泡毛细血管细胞类型,肺泡边缘细胞
中性粒细胞在这里,我们介绍了新的靶向标签,可以大量集中M-LACs在肺泡
中性粒细胞有了将拉克靶向内皮细胞和中性粒细胞的新能力,我们现在可以
回答ARDS生物学(目标1)和一般药理学(目标2)的基本问题,
从根本上改善M-LAC作为ARDS的治疗方法(目标3)。目的1:体外人肺和体内
在ARDS小鼠模型中,我们定量了与未处理小鼠相比,边缘中性粒细胞的相对数量。
例,我们将测量中性粒细胞和内皮细胞对M-LACs的吸收情况。目标2:我们将测试
靶向药物输送的“仓库理论”,即药物有效地从靶细胞转移到靶细胞,
他们的邻居。我们将测试药物是否作用于中性粒细胞(例如,中性粒细胞弹性蛋白
抑制剂)将改善ARDS样表型,如果靶向内皮细胞,则相同或更差,
反之亦然目的3:我们将确定联合治疗的原则。我们假设,
有效的组合将是一对中性粒细胞和内皮调节药物(例如,作为
与2种内皮调节药物相反)。在这些研究结束时,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治疗方法,我们将在多种小鼠模型中进行测试,
ARDS和人的肺。
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Nano-War Against Complement Proteins.
- DOI:10.1208/s12248-021-00630-9
- 发表时间:2021-09-10
- 期刊:
- 影响因子:0
- 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:
- 影响因子:0
- 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:
- 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:
- 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
- 通讯作者: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:
- 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
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Jacob Brenner其他文献
Jacob Brenner的其他文献
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{{ truncateString('Jacob Brenner', 18)}}的其他基金
miRNA-Nanotechnology as a novel regenerative therapy for lymphangioleiomyomatosis
miRNA-纳米技术作为淋巴管平滑肌瘤病的新型再生疗法
- 批准号:
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防止阿片类药物过量死亡的 DOVE 装置:可感应过量并自动注射纳洛酮的臂带
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10485568 - 财政年份:2023
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Next-generation nanomedicine for acute ischemic stroke
治疗急性缺血性中风的下一代纳米药物
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Controlling complement to unleash nanomedicine for acute critical illnesses
控制补体释放纳米药物治疗急性危重疾病
- 批准号:
10557895 - 财政年份:2022
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Controlling complement to unleash nanomedicine for acute critical illnesses
控制补体释放纳米药物治疗急性危重疾病
- 批准号:
10340537 - 财政年份:2022
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RBC-mediated mopping of cytokines for the treatment of pneumonia
红细胞介导的细胞因子清除治疗肺炎
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RBC-mediated mopping of cytokines for the treatment of pneumonia
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- 批准号:
10353073 - 财政年份:2021
- 资助金额:
$ 40.63万 - 项目类别:
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:
10030992 - 财政年份:2020
- 资助金额:
$ 40.63万 - 项目类别:
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:
10466854 - 财政年份:2020
- 资助金额:
$ 40.63万 - 项目类别:
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