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:10030992
- 负责人:
- 金额:$ 40.5万
- 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:AcuteAddressAdult Respiratory Distress SyndromeAdverse drug effectAir SacsAlveolarAlveolar CellAmericanAntibodiesBindingBiologyBloodBlood capillariesCellsClinical TrialsCombined Modality TherapyDoseDrug CarriersDrug CombinationsDrug Delivery SystemsDrug SynergismDrug TargetingDrug toxicityEndothelial CellsEndotheliumFailureFunctional disorderGoalsHumanImatinibImpairmentInhalationLabelLeftLipidsLiposomesLiquid substanceLungMeasuresMediatingMediator of activation proteinModelingMusNanotechnologyNebulizerOrganOrgan failurePathway interactionsPatientsPharmaceutical PreparationsPharmacologyPharmacotherapyPhenotypePublishingPulmonary Artery BranchRoleSignal PathwayStructure of parenchyma of lungTestingTherapeuticTherapeutic EffectTherapeutic IndexTimeTissue BanksToxic effectTransplantationTreatment EfficacyWorkbasecell typedesignhuman modelimprovedin vivoinflammatory lung diseaseinventionmouse modelnanocarriernanomedicinenanometerneutrophilneutrophil elastase inhibitornovelnovel therapeuticspharmacokinetic modelpreventresponsescreeningside 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.
抽象的
在炎症性肺部疾病ARDS的临床试验中,数十种药物失败(急性
呼吸窘迫综合征),很大程度上是由于ARDS的3种药物挑战:ARDS
患者患有多系统器官衰竭,因此无法忍受脱靶药物副作用;列
液体覆盖肺泡可防止有效的遗传递送;数十个信号通路是弧形的基础,
因此,调制一个人将无法使用。为了克服这三个挑战,我们设计了M-Lacs,
是100纳米脂质球(脂质体),装有多种药物,并涂有靶向
导致它们大量积聚在肺泡(肺部气囊)的毛细血管中的标签。
我们以前已经发表过关于针对肺泡内皮细胞的M-LAC的好处,但已有
长期看到需要针对其他主要牙槽毛细管细胞类型,牙槽缘缘
中性粒细胞。在这里,我们介绍了可以将M-LAC大量集中在肺泡中的新目标标签
中性粒细胞。具有将紫胶靶向内皮和中性粒细胞的新能力,我们现在可以
回答ARDS生物学(AIM 1)和一般药理学(AIM 2)的基本问题,而
从根本上改善了M-LAC作为ARDS疗法(AIM 3)。目标1:在体内人类肺和体内
ARDS的小鼠模型,我们量化了与天真的中性粒细胞相对数量的相对数量
情况,我们将测量中性粒细胞和内皮占M-LAC的含量。目标2:我们将测试
靶向药物输送的“仓库理论”,该药物说药物有效地从靶细胞洗脱到
他们的邻居。我们将测试药物是否在中性粒细胞中起作用(例如中性粒细胞弹性酶
抑制剂)如果靶向内皮细胞,则可以改善类似ARDS样的表型,并且更糟
反之亦然。目标3:我们将确定组合疗法的原理。我们假设最多
有效的组合将是一对嗜中性粒细胞和内皮调节药物(例如,AS
反对2种内皮调节药物)。到这些研究结束时,我们将发现新的
ARDS生物学并回答了药理学中的基本问题。此外,我们将有
为ARDS创建了高度优化的疗法,我们将在多个鼠标模型中测试
ARDS和人类肺部。
项目成果
期刊论文数量(0)
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Jacob Brenner其他文献
Jacob Brenner的其他文献
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