Exploiting an endogenous transcytotic pathway for oral drug delivery

利用内源性转胞吞途径进行口服药物递送

• 批准号: 9927660
• 负责人: THOMAS ANCHORDOQUY
• 金额: $ 47.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927660
• 关键词: Acids; Activities of Daily Living; Albumins; Amphotericin; Antibiotics; Antibodies; Antifungal Agents; Binding; Bioavailable; Biodistribution; Biological Assay; Biological Availability; Blood; Blood Circulation; Carbohydrates; Cattle; Clinical Research; Clinical Trials; Consumption; Contracts; Cost Savings; Data; Disease; Dose; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug vehicle; Elderly; Enzymes; Equipment; Exhibits; Gastrointestinal tract structure; Glycolipids; Half-Life; Harvest; Health; Healthcare Systems; Home environment; Hospitals; Human; Human Milk; Human Resources; Immune; Immunocompetent; Immunoglobulin Fragments; Immunoglobulin G; Immunoglobulins; Infection; Infusion procedures; Inpatients; Insulin; Intravenous infusion procedures; Kinetics; Life; Ligands; Lipids; Liposomes; Malignant Neoplasms; Mediating; MicroRNAs; Milk; Molecular; Monitor; Mus; Neonatal; Oral; Oral Administration; Outcome; Particulate; Pathway interactions; Patient Monitoring; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Preparation; Process; Quality of life; Research; Resistance; Risk; Role; Skilled Nursing Facilities; Sterility; Stomach; Suggestion; System; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Training; Travel; Vancomycin; Vascular Endothelium; Vesicle; Work; absorption; base; cost; cross reactivity; design; exosome; experimental study; gastrointestinal; gastrointestinal epithelium; improved; in vivo; liquid chromatography mass spectrometry; metabolomics; microbial; mouse model; nanoparticle; neonatal Fc receptor; particle; peptide drug; practical application; receptor; small molecule; transcytosis; tumor; uptake

Project Summary The work described in this proposal investigates the potential of exosomes harvested from cow's milk to be used as oral delivery vehicles for drugs that currently require infusion therapy. Our central hypothesis is that milk exosomes utilize the FcRn receptor that is constitutively expressed throughout life in humans. In addition, previous studies have documented that bovine IgG cross-reacts with human FcRn, and clinical trials have documented the presence of bovine miRNAs in the blood of patients who consumed milk. Although the FcRn receptor has been shown to facilitate the uptake of Fc-targeted nanoparticles across the gastrointestinal epithelium, the ability of exosomes to exploit this pathway has yet to be considered or investigated. Our preliminary data suggest that the oral bioavailability of exosome cargo exceeds 10%, and that uptake is greatly reduced if free bovine IgG is co-administered with milk exosomes; consistent with FcRn-mediated absorption. Previous studies have suggested that exosomes are transcytosed across the gastrointestinal epithelium as intact particles, and our results demonstrate that orally- administered, iRGD-targeted exosomes significantly enhance tumor delivery. In addition to the practical application of reducing the need for infusion therapy, the proposed experiments explore the mechanism by which transcytosis across the gastrointestinal epithelium is accomplished, and strives to identify unknown factors that have been proposed to contribute to this process.

项目摘要 这项建议中描述的工作调查了收获的外切体的潜力。 将牛奶用作口服给药载体，目前需要 输液疗法。我们的中心假设是牛奶外切体利用FcRN受体 这在人类的一生中都有结构性的表达。此外，此前的研究表明， 已经证明牛的免疫球蛋白与人的FcRN发生交叉反应，临床试验已经 记录了吸食的患者血液中存在牛miRNAs 牛奶。尽管FcRN受体已被证明有助于Fc靶向的摄取 胃肠道上皮中的纳米颗粒，外切体利用这一点的能力 这条途径还有待考虑或调查。我们的初步数据表明 外切体货物的口服生物利用度超过10%，如果 游离牛免疫球蛋白与牛奶外切体联合给药；与FcRN介导的一致 吸收。先前的研究表明，胞外体可以跨细胞转运 胃肠道上皮作为完整的颗粒，我们的结果表明，口服- 给药后，IRGD靶向外切体显著增强了肿瘤的递送。此外 为了减少输液治疗的实际应用，建议 实验探索穿过胃肠道的细胞穿透的机制 上皮细胞完成了，并努力识别未知的因素，已经 提议为这一进程作出贡献。