Vascular Targeting of Nanocarriers for RNA
RNA 纳米载体的血管靶向
基本信息
- 批准号:10560629
- 负责人:
- 金额:$ 79.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-05 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Lung InjuryAffinityAnti-Inflammatory AgentsAntibodiesAreaBenchmarkingBindingBiologicalBiological ProductsBiological Response Modifier TherapyBlood VesselsBrainCell Adhesion MoleculesCell LineCell membraneCellsCerebrovascular systemCerebrumClinicalCoupledDevelopmentDiseaseDoseDrug Delivery SystemsDrug KineticsElementsEncephalitisEndocytosisEndothelial CellsEndotheliumEngineeringEpitopesExtrahepaticFlow CytometryFormulationFunctional disorderFutureGene ProteinsGoalsHumanInflammationIntercellular adhesion molecule 1IsotopesLigandsLiverLungMapsMedicalMessenger RNAMethodsMicroscopyModelingModificationMusNanotechnologyOrganPharmacotherapyPilot ProjectsProteinsPulmonary InflammationRNARNA deliveryRecombinantsReporterSignal TransductionSiteSpecific qualifier valueSpleenStrokeSurfaceTestingTherapeuticThrombomodulinThrombosisTimeTissuesTransgenesTranslatingTranslationsVascular Cell Adhesion Molecule-1cell typeclinical applicationgene synthesisin vivointravenous injectionlead candidatelipid nanoparticlemouse modelnanobodiesnanocarriernanomedicinenanoparticlenanotechnology platformnovelnovel strategiesprophylacticprotective effectreal-time imagesspatiotemporaltargeted treatmenttherapeutic genethrombotictransgene expressionuptake
项目摘要
Clinical approval of Lipid Nano Particles (LNP) for RNA heralded the advent of nanotechnology-
based pharmacotherapy. Yet, RNA delivery to extra-hepatic sites remains a major unmet challenge.
Weissman pioneered modifications of mRNA providing effective translation in diverse cell types, while
Muzykantov introduced “vascular targeting”, nanomedicine strategy for drug delivery to desired areas
in the vasculature. Here we converge these advances to devise nanocarriers targeting RNA to
desired sites of transgene synthesis and therapeutic action. We found that ligands of Inter-Cellular
Adhesion Molecule-1 (ICAM) conjugated to nanocarriers, direct ICAM-LNP (ILNP) to accumulate in
lungs, especially, in the inflamed lungs, with trivial cerebral uptake. In opposite, LNP targeting to
Vascular Cell Adhesion Molecule-1 (VCAM) provides trivial pulmonary uptake of VCAM-LNP (VLNP),
and selective uptake in the inflamed brain, surpassing the benchmarks by orders of magnitude. VLNP
loaded with mRNA encoding endothelial multifunctional anti-thrombotic and anti-inflammatory protein
thrombomodulin (TM) provides transgene synthesis and protective effect in the inflamed CNS
unrivaled by other agents. We will characterize and if needed reiteratively re-engineer targeting
features of this powerful nanotechnology platform, by pursuing the following Specific Aims. Aim 1:
Multi-scale spatiotemporal mapping of vascular targeting of ILNP and VLNP. Using isotope tracing
and real time imaging, in vivo microscopy and flow cytometry, we will define PK/BD, dynamics of LNP
localization and reporter transgene activity in the sites of desirable therapeutic action. Aim 2:
Targeting therapeutic thrombomodulin RNA to lung and brain. We will characterize salient parameters
of TM transgene expression, beneficial and unintended effects of ILNP and VLNP in naive mice and
in mouse models of pulmonary and cerebral inflammation. Aim 3: Translational development of LNP.
We will upgrade LNP to clinically applicable format via site-specific conjugation of small recombinant
ligands. This study will define key specification parameters of a novel nanotechnology platform for
selective delivery of RNA to desirable cells and cellular compartments in brain, lungs and likely other
organs. It will establish proof of principle for a new nanomedicine approach for effective, specific and
safe biological pharmacotherapy of ALI and stroke, with future expansion to other diseases.
脂质纳米颗粒(LNP)用于RNA的临床批准预示着纳米技术的到来--
以药物治疗为基础。然而,将RNA运送到肝外部位仍然是一个尚未满足的主要挑战。
魏斯曼率先对信使核糖核酸进行修饰,在不同的细胞类型中提供了有效的翻译,而
Muzykantov介绍了“血管靶向”,即将药物输送到所需区域的纳米药物战略
在血管系统中。在这里,我们汇集了这些进展,以设计针对RNA的纳米载体来
转基因合成和治疗作用的理想部位。我们发现细胞间的配体
黏附分子-1(ICAM)偶联到纳米载体上,引导ICAM-LNP(ILNP)在
肺部,特别是发炎的肺部,有少量的大脑摄取。相反,LNP的目标是
血管细胞黏附分子-1(VCAM)提供对VCAM-LNP(VLNP)的少量肺摄取,
在发炎的大脑中选择性摄取,超过基准数量级。VLNP
携带编码血管内皮细胞多功能抗血栓抗炎蛋白的mRNA
血栓调节蛋白(TM)在炎症的中枢神经系统中提供转基因合成和保护作用
是其他代理商所无法比拟的。我们将确定目标的特征,并在需要时反复重新设计目标
这一强大的纳米技术平台的特点,通过追求以下具体目标。目标1:
ILNP和VLNP血管靶向的多尺度时空标测。使用同位素示踪
实时成像,活体显微镜和流式细胞术,我们将定义PK/BD,LNP的动力学
在理想的治疗作用部位的定位和报告转基因活性。目标2:
靶向肺和脑的治疗性血栓调节蛋白RNA。我们将描述显著参数
对转基因表达的影响,ILNP和VLNP对幼鼠和
在小鼠的肺部和脑部炎症模型中。目标3:LNP的翻译发展。
我们将通过小重组蛋白的定点结合将LNP升级为临床适用的形式
配基。这项研究将确定一种新型纳米技术平台的关键规格参数
选择性地将RNA递送到所需的细胞和脑、肺以及可能的其他组织中的细胞室
器官。它将为一种新的纳米医学方法建立原则证明,以实现有效、特异和
ALI和卒中的安全生物药物治疗,未来将扩展到其他疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Vladimir R Muzykantov其他文献
Vladimir R Muzykantov的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Vladimir R Muzykantov', 18)}}的其他基金
Dual drug delivery to lung/blood interface in respiratory infections.
在呼吸道感染中向肺/血液界面双重给药。
- 批准号:
10179690 - 财政年份:2021
- 资助金额:
$ 79.28万 - 项目类别:
Dual drug delivery to lung/blood interface in respiratory infections.
在呼吸道感染中向肺/血液界面双重给药。
- 批准号:
10614476 - 财政年份:2021
- 资助金额:
$ 79.28万 - 项目类别:
Dual drug delivery to lung/blood interface in respiratory infections.
在呼吸道感染中向肺/血液界面双重给药。
- 批准号:
10393610 - 财政年份:2021
- 资助金额:
$ 79.28万 - 项目类别:
Vascular delivery of nanocarriers by erythrocyres
红细胞对纳米载体的血管输送
- 批准号:
9922385 - 财政年份:2018
- 资助金额:
$ 79.28万 - 项目类别:
Vascular delivery of nanocarriers by erythrocyres
红细胞对纳米载体的血管输送
- 批准号:
10153877 - 财政年份:2018
- 资助金额:
$ 79.28万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 79.28万 - 项目类别:
Continuing Grant