Homogenized, engineered extracellular vesicles for intracranial targeting
用于颅内靶向的均质化、工程化细胞外囊泡
基本信息
- 批准号:10659682
- 负责人:
- 金额:$ 53.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-04 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAstrocytesBehaviorBiochemicalBiodistributionBiologicalBiological AssayBiological AvailabilityBiological ProcessBioreactorsBlood - brain barrier anatomyBrainBreast Cancer CellCancer cell lineCell LineCellsChemicalsClinicalComplexDiseaseDisseminated Malignant NeoplasmDoseDrug Delivery SystemsDrug TargetingEndotheliumEngineeringExhibitsFDA approvedFailureFeedbackFormulationFoundationsGlioblastomaGoalsGood Manufacturing ProcessHalf-LifeHeterogeneityHybridsImageImmuneLabelLibrariesLigandsLiposomesMalignant NeoplasmsMalignant neoplasm of brainMeasuresMechanicsMediatingMedicineMethodsMicrofluidicsModelingMolecularMusNeurodegenerative DisordersNeurogliaNeuronsPathway interactionsPatientsPenetrationPerformancePharmaceutical PreparationsPhase I Clinical TrialsPopulationPropertyProteinsRNAReportingResearchSafetyShapesSolidSourceSterilityStructureSystemTechniquesTestingTherapeuticTissuesToxic effectTranslatingTreatment EfficacyTropismVisionWorkbiomaterial compatibilityblood-brain barrier crossingcell typeclinical practicecombatcontrolled releasedelivery vehicledesigndrug release profileefficacy studyexpectationextracellular vesiclesfunctional improvementimmune clearancein vivoinnovationinterestloss of functionmimeticsmouse modelnanoarchitecturenanocarriernanomaterialsnanoparticlenanoscalenervous system disorderneuralnext generationnovelnovel strategiesparticlepersonalized carepharmacokinetics and pharmacodynamicsreceptorsafety studysafety testingsuccesssynthetic drugtemozolomidetooltranscytosistumoruptake
项目摘要
PROJECT SUMMARY/ABSTRACT
The objective of the proposed research is to engineer a targeted biological nanoparticle platform with high
intracranial delivery and glial cell targeting for broad applicability in drug delivery and imaging. A great deal of
work has already been accomplished elucidating the ability of certain extracellular vesicles (EVs) to cross
endothelial barriers, especially the blood-brain barrier (BBB). Other work has established that EVs exhibit
excellent tropism towards particular tissues and cell types. The focus of this proposal is to understand the
mechanisms by which certain EV subpopulations accomplish these feats, and to engineer them into a hybrid
liposome-EV drug delivery platform. Given the plethora of recent research into EV structure and function, it is
well known that they exhibit considerable compositional heterogeneity. But fundamental questions still exist as
to how EV prescribed functions differ across these subpopulations. It is likely that off-target effects and
inefficiencies in capturing native EV functions with engineered mimetics are due to their substantial
heterogeneity. Our first hypothesis is that homogenization of EVs towards a narrow size range with uniform
biomolecular content will result in a more potent and controllable drug delivery platform that maintains native EV
function yet reduces off-target toxicity. Our second hypothesis is that fusion of homogenized EVs and
liposomes with various functions (i.e., efficient BBB permeation through receptor mediated transcytosis) will
deliver an engineered product combining desired functions. We plan on addressing these hypotheses through
rigorous engineering to homogenize EVs (Aim 1) alongside biochemical assays to detangle the mechanisms
important for EV intracranial delivery. We will utilize EVs isolated from gliatropic “experts”, namely a vast library
of glioblastoma (GBM) patient derived primary cell lines, brain-metastasizing breast cancer cells, and other glial
and neuronal cells like astrocytes and neurons. Key molecular players important for intracranial delivery identified
from those studies will feedback into synthesis of engineered EVs (eEVs) via subsequent fusion with carrier EVs
(Aim 2). For the engineered eEV product, we will also incorporate synthetic liposomes decorated with known
ligands to trigger receptor mediated transcytosis through the BBB endothelial layer. To provide the greatest
opportunity to measure efficiency of functional intracranial delivery, we plan to load formulated, labeled, and
homogenized eEVs with a chemotherapeutic payload and determine drug-release profile, biodistribution, and
efficacy in healthy mice with intact BBBs and then an orthotopic GBM model (Aim 3). The proposed work is
important because it seeks to eliminate the highly confounding factor of particle-to-particle variability plaguing
effective application of EVs as potent drug-delivery vehicles. Success in homogenizing eEVs will result in an
increased understanding of their biological function and assist in their application to combat a wide variety of
neurological disorders where current drug delivery approaches are thwarted by low intracranial delivery.
项目总结/文摘
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 }}
Randy Carney其他文献
Randy Carney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('Randy Carney', 18)}}的其他基金
Bottom-up, high-throughput prototyping of extracellular vesicle mimetics using cell-free synthetic biology
使用无细胞合成生物学对细胞外囊泡模拟物进行自下而上的高通量原型设计
- 批准号:
10638114 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
A miniaturized neural network enabled nanoplasmonic spectroscopy platform for label-free cancer detection in biofluids
微型神经网络支持纳米等离子体光谱平台,用于生物流体中的无标记癌症检测
- 批准号:
10658204 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
SERS diagnostics platform for liquid bioapsy analysis of tumor-associated exosomes
用于肿瘤相关外泌体液体活检分析的 SERS 诊断平台
- 批准号:
9973569 - 财政年份:2020
- 资助金额:
$ 53.36万 - 项目类别:
SERS diagnostics platform for liquid bioapsy analysis of tumor-associated exosomes
用于肿瘤相关外泌体液体活检分析的 SERS 诊断平台
- 批准号:
10377437 - 财政年份:2020
- 资助金额:
$ 53.36万 - 项目类别:
SERS diagnostics platform for liquid bioapsy analysis of tumor-associated exosomes
用于肿瘤相关外泌体液体活检分析的 SERS 诊断平台
- 批准号:
10593985 - 财政年份:2020
- 资助金额:
$ 53.36万 - 项目类别:
相似国自然基金
Ascl1介导Wnt/beta-catenin通路在TLE海马硬化中反应性Astrocytes异常增生的作用及调控机制
- 批准号:31760279
- 批准年份:2017
- 资助金额:35.0 万元
- 项目类别:地区科学基金项目
相似海外基金
The contribution of astrocytes in behavioral flexibility
星形胶质细胞对行为灵活性的贡献
- 批准号:
24K18245 - 财政年份:2024
- 资助金额:
$ 53.36万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidating endolysosomal trafficking dysregulation induced by APOE4 in human astrocytes
阐明人星形胶质细胞中 APOE4 诱导的内溶酶体运输失调
- 批准号:
10670573 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
DNA methylation signatures of Alzheimer's disease in aged astrocytes
老年星形胶质细胞中阿尔茨海默病的 DNA 甲基化特征
- 批准号:
10807864 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
Genetically-Encoded, Non-Invasive and Wireless Modulation of Calcium Dynamics in Astrocytes With Spatiotemporal Precision and Depth
具有时空精度和深度的星形胶质细胞钙动态的基因编码、非侵入性无线调节
- 批准号:
10562265 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
Accelerating Functional Maturation of Human iPSC-Derived Astrocytes
加速人 iPSC 衍生的星形胶质细胞的功能成熟
- 批准号:
10699505 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
Defining cell type-specific functions for the selective autophagy receptor p62 in neurons and astrocytes
定义神经元和星形胶质细胞中选择性自噬受体 p62 的细胞类型特异性功能
- 批准号:
10676686 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
Astrocytes control the termination of oligodendrocyte precursor cell perivascular migration during CNS development
星形胶质细胞控制中枢神经系统发育过程中少突胶质细胞前体细胞血管周围迁移的终止
- 批准号:
10727537 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
Multispectral Imaging of Neurons and Astrocytes: Revealing Spatiotemporal Organelle Phenotypes in Health and Neurodegeneration
神经元和星形胶质细胞的多光谱成像:揭示健康和神经退行性疾病中的时空细胞器表型
- 批准号:
10674346 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
The role of lateral orbitofrontal cortex astrocytes in alcohol drinking
外侧眶额皮质星形胶质细胞在饮酒中的作用
- 批准号:
10823447 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别:
Investigating the role of diazepam binding inhibitor (DBI) in astrocytes and neural circuit maturation
研究地西泮结合抑制剂 (DBI) 在星形胶质细胞和神经回路成熟中的作用
- 批准号:
10567723 - 财政年份:2023
- 资助金额:
$ 53.36万 - 项目类别: