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: 9750224
• 负责人: THOMAS ANCHORDOQUY
• 金额: $ 49.88万
• 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/9750224
• 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; Epithelial; 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.

项目概要 该提案中描述的工作调查了收获的外泌体的潜力 将牛奶用作目前需要的药物的口服给药载体 输液治疗。我们的中心假设是牛奶外泌体利用 FcRn 受体 这在人类的整个生命过程中都有所组成性表达。此外，之前的研究 已记录牛 IgG 与人 FcRn 发生交叉反应，并且临床试验已证实 记录了食用牛 miRNA 的患者血液中的存在 牛奶。尽管 FcRn 受体已被证明可以促进 Fc 靶向的摄取 纳米颗粒穿过胃肠道上皮，外泌体利用这种能力 途径尚待考虑或研究。我们的初步数据表明 外泌体的口服生物利用度超过 10%，并且如果 游离牛 IgG 与牛奶外泌体共同给药；与FcRn介导一致 吸收。先前的研究表明，外泌体可以跨胞吞 胃肠道上皮作为完整的颗粒，我们的结果表明口服 施用后，iRGD 靶向的外泌体显着增强肿瘤递送。此外 为了减少输液治疗需求的实际应用，建议 实验探讨了跨胃肠道转胞吞作用的机制 上皮细胞已完成，并努力识别已被研究的未知因素 提议为这一进程做出贡献。