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Nanohydrocyclones for scalable extracellular vesicle purification and drug loading

用于可扩展细胞外囊泡纯化和药物装载的纳米水力旋流器

基本信息

批准号：
10458751
负责人：
Don L DeVoe
金额：
$ 19.14万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
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：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458751
关键词：
3D Print Acoustics Acute Lung Injury Address Biological Assay Biological Products Biomanufacturing Cardiovascular Diseases Cardiovascular system Cells Clinic Development Device Designs Devices Drug Carriers Elements Encapsulated Filtration Fostering Generations Harvest In Situ Lasers Liposomes Lung Lung diseases Methods MicroRNAs Microdialysis Microfluidic Microchips Microfluidics Miniaturization Modality Modeling Molecular Sieve Chromatography Myocardial Infarction Myocardial Ischemia Natural regeneration Patient Care Patients Performance Pharmaceutical Preparations Positioning Attribute Preparation Process Production Proteins Pulmonary Fibrosis Reperfusion Injury Reporting Research Personnel Resources Respiratory Disease Route Safety Scheme Small Interfering RNA Source Stroke System Techniques Technology Therapeutic Therapeutic Agents Therapeutic Effect Time Translations Ultracentrifugation Vesicle Writing base clinical translation cost design drug development extracellular vesicles improved interest lung injury mesenchymal stromal cell microdevice nanoscale nanovesicle novel strategies novel therapeutics pH gradient particle pre-clinical preclinical efficacy product development prototype repaired small molecule success therapeutic development translational potential wound healing

项目摘要

PROJECT SUMMARY Next-generation therapeutics based on extracellular vesicles (EVs) as biologically-derived drug carriers have emerged as a highly promising route to the treatment of a wide range of cardiovascular and respiratory diseases. Despite the broad interest in EV-based drug development, it is increasingly clear that existing methods for preparing therapeutic EVs suffer from a number of constraints that present a significant barrier to clinical translation. In addition to low throughput, long processing times, and labor-intensive operational steps, established separation methods suffer from poor separation efficiencies that result in vesicle loss, size bias, and co-elution of soluble proteins that contaminate the resulting nanovesicle drug. This latter challenge is of particular concern, as the presence of soluble proteins complicates interpretations of efficacy and safety. An additional issue is that while microRNAs (miRNAs) encapsulated within EVs represent a key component conferring therapeutic effect, the intrinsic concentration of miRNA in EVs is extremely low. As a result, effective EV therapies require that exogenous miRNA be loaded into the vesicles to increase potency. While a number of EV cargo loading techniques have been developed, many of these methods demand to introduction of external electrical or acoustic energy that can damage the vesicles and their cargo. Furthermore, existing EV separation and loading techniques require multiple processing steps that are not inherently scalable, increasing development cost and time, and presenting a practical challenge for moving EV therapeutics beyond the preclinical stage. In this R21 project, we propose a new scalable approach to EV separation and drug loading that is compatible with the needs for clinical translation, addressing a significant bottleneck in EV biomanufacturing and enabling a single-step streamlined workflow for the preparation of high potency EV therapeutics. The proposed technology consists of a single device integrating efficient size-based EV separation with drug loading into a scalable, automated, and self-contained process. The platform will leverage a miniature hydrocyclone technology previously developed by our team that has the potential to isolate EVs in the 30-150 nm range in a passive flow- through microfluidic chip. An array of hydrocyclones operating at high flow rates on the order of 1 mL/min will be combined with integrated microfluidic counterflow microdialysis elements to implement a proven pH-gradient- based loading method developed by our group to control EV cargo encapsulation. The scalable platform will enable in-line loading of purified EVs from any cell or biofluid source, using a simple workflow expected to significantly reduce therapeutic EV processing time and cost. The resulting system is further expected to improve vesicle purity and cargo loading efficiency, supporting the development and translation of a new class of EV therapeutics with the potential to impact treatment of a broad range of cardiovascular and respiratory diseases.

项目总结