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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：
Randy Carney
金额：
$ 53.36万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
https://reporter.nih.gov/project-details/10659682
关键词：
Address Astrocytes Behavior Biochemical Biodistribution Biological Biological Assay Biological Availability Biological Process Bioreactors Blood - brain barrier anatomy Brain Breast Cancer Cell Cancer cell line Cell Line Cells Chemicals Clinical Complex Disease Disseminated Malignant Neoplasm Dose Drug Delivery Systems Drug Targeting Endothelium Engineering Exhibits FDA approved Failure Feedback Formulation Foundations Glioblastoma Goals Good Manufacturing Process Half-Life Heterogeneity Hybrids Image Immune Label Libraries Ligands Liposomes Malignant Neoplasms Malignant neoplasm of brain Measures Mechanics Mediating Medicine Methods Microfluidics Modeling Molecular Mus Neurodegenerative Disorders Neuroglia Neurons Pathway interactions Patients Penetration Performance Pharmaceutical Preparations Phase I Clinical Trials Population Property Proteins RNA Reporting Research Safety Shapes Solid Source Sterility Structure System Techniques Testing Therapeutic Tissues Toxic effect Translating Treatment Efficacy Tropism Vision Work biomaterial compatibility blood-brain barrier crossing cell type clinical practice combat controlled release delivery vehicle design drug release profile efficacy study expectation extracellular vesicles functional improvement immune clearance in vivo innovation interest loss of function mimetics mouse model nanoarchitecture nanocarrier nanomaterials nanoparticle nanoscale nervous system disorder neural next generation novel novel strategies particle personalized care pharmacokinetics and pharmacodynamics receptor safety study safety testing success synthetic drug temozolomide tool transcytosis tumor uptake

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