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

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)
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会议论文数量(0)
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Randy Carney其他文献

Randy Carney的其他文献

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{{ 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:

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