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Developing IL-10 encapsulated exosomes as novel therapeutics for spontaneous preterm birth

开发 IL-10 封装的外泌体作为自发性早产的新型疗法

基本信息

批准号：
10592047
负责人：
Ananth kumar Kammala
金额：
$ 8万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-09 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592047
关键词：
37 weeks gestation Address Amniotic Fluid Animals Anti-Inflammatory Agents Bacteria Bacterial Infections Biodistribution Biogenesis Biological Birth CD81 gene Cd68 Cells Cervical Ripening Cervix Uteri Clinical Trials Data Development Dexamethasone Dose Drug Delivery Systems Drug Transport Dyes Electron Microscope Electroporation Encapsulated Engineering Ensure Escherichia coli Euthanasia Exclusion Exposure to Fetal Membranes Fetal Reduction Fetal Tissues Fetus Future Hour Image Immune Immune Tolerance In Vitro Incidence Infection Inflammation Inflammatory Inflammatory Response Interleukin-10 Intervention Intravenous Investigational Drugs Label Lipopolysaccharides Macrophage Maternal-Fetal Exchange Maternal-Fetal Medicine Units Network Mediating Metabolic Methods Modeling Monitor Morphology Mothers Mus NF-kappa B Neonatal Mortality Pathologic Pharmaceutical Preparations Physiological Placenta Plasma Plasmids Pregnancy Pregnancy Outcome Premature Birth Production Prolonged Pregnancy Property Proteins Recombinants Risk Risk Factors Sampling Surface Teratogens Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Transcription Coactivator Translating Tropism Ultracentrifugation United States Uterine Contraction Uterus cervical remodeling chemokine cohort confocal imaging cost effective cytokine cytotoxicity delivery vehicle design drug development drug testing effective therapy efficacy evaluation efficacy testing engineered exosomes exosome extracellular extracellular vesicles fetal human fetal cells imaging system improved in vivo in vivo imaging system innovation lipophilicity mouse model nanoparticle neonatal morbidity neonate novel therapeutics risk minimization success trafficking

项目摘要

ABSTRACT Present therapeutic agents are designed to inhibit the myometrial contractions or cervical ripening to delay delivery in the risk of spontaneous preterm birth (PTB). These approaches have limited success in reducing the overall rate of PTB, which his ~11% in the USA. A novel drug delivery system needs to be designed to improve pregnancy outcomes. Successful pregnancy is determined by regulatory mechanisms at the F-M, ensuring that both innate and adaptive immune cells aptly support fetoplacental development by balancing inflammation while remodeling uterine tissues. Immune dysregulation, primarily mediated by a fetal inflammatory response to pregnancy-associated risk factors (eg, infections), leads to PTB. The inability of drugs to cross feto-maternal interface barriers to treat both the mother and her fetus, as well as lack of proper ways of testing drug transport, metabolic changes, teratogenicity, and cytotoxicity, has hindered PTB drug development. Using, the naturally occurring anti-inflammatory cytokine interleukin (IL)-10, enclosed in exosomes (extracellular vesicles, 40–160 nm) engineered by electroporation (eIL-10), IL-10 crossed the placental barrier, delayed PTB induced by LPS, and reduced fetal inflammatory response compared to LPS alone. However, the method of electroporation will alter the tropism of exosomes, and the production of recombinant IL-10 loaded exosomes is very expensive. To overcome these electroporation limitations, we developed an alternate approach to produce large quantities of IL-10 enriched exosomes by incorporating IL- 10 plasmid into mouse macrophages (RAW 264.7 cells) and stimulating them with dexamethasone (Dex). Dex induces IL-10 production and will be packaged in large quantities in exosomes (eIL-10). This approach has overcome the limitation of electroporation and increased the efficiency of IL-10 packaging in exosomes during biogenesis. Thus, the approach minimizes alterations of exosome proteins, and the production of eIL-10 will be cost-effective. We will test the hypothesis that eIL-10 will reduce the incidence of ascending infection (E. coli) induced PTB mouse model. We propose the following aims to test our hypothesis. 1) To characterize eIL-10 and determine its functional activity in in vitro studies, 2) To determine efficacy and biodistribution of exosomal IL-10 (eIL-10) in in vivo studies. Our innovative approach will prolong pregnancy and can translate into a critically needed specific interventional strategy to decrease infection/inflammation associated with PTB and thereby improve pregnancy outcomes.

摘要