In-Vivo Monitoring of Therapeutic Drug Transport Across Biological Barriers

治疗药物跨生物屏障转运的体内监测

• 批准号: 10094296
• 负责人: Netzahualcoyotl Arroyo Curras
• 金额: $ 36.75万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10094296
• 关键词: Acidity; Affect; Aminoglycosides; Amoxicillin; Ampicillin; Antibiotic Prophylaxis; Antibiotics; Bacteria; Behavior; Biological; Biopsy; Blood; Blood capillaries; Brain; Brain Injuries; Brain region; Cell Line; Cerebrospinal Fluid; Characteristics; Chemical Structure; Chemicals; Chemoreceptors; Clinical; Complex; Dangerousness; Data; Detection; Development; Dose; Drug Kinetics; Drug Transport; Endothelium; Environment; Exposure to; Extracellular Space; Family; Foundations; Future; Gentamicins; Glycopeptide Antibiotics; Glycopeptides; Goals; Hippocampus (Brain); Implant; In Vitro; Industry; Infection; Kanamycin; Kinetics; Knowledge; Libraries; Liver; Maps; Measurement; Measures; Mediating; Medical; Membrane; Methodology; Modeling; Molecular; Monitor; Monobactams; Nature; Operative Surgical Procedures; Organ; Penetrating Brain Injury; Penetration; Penicillin G; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Preparation; Prophylactic treatment; Prostate; Prostatic; Rattus; Regimen; Research; Research Personnel; Resistance development; Resources; Sampling; Structure; Structure of jugular vein; Testing; Thalamic structure; Therapeutic; Therapeutic Agents; Time; Tissues; Tobramycin; Transport Process; Travel; Vancomycin; Work; aptamer; base; beta-Lactams; blood cerebrospinal fluid barrier; chemical property; cost; drug development; improved; in vivo; in vivo evaluation; in vivo monitoring; novel therapeutics; passive transport; precision drugs; predictive modeling; prevent; programs; real time monitoring; response; sensor; sensor technology; side effect; standard of care; temporal measurement; therapeutically effective; tumor; uptake; wearable sensor technology; wound

Project Summary The ability of therapeutic drugs to access specific organs strongly depends on the nature of the blood-tissue barrier at said organs. The prostate and brain, for example, have tight barriers with no intercellular gaps, and most drugs cannot permeate them at sufficiently high levels to be therapeutically effective. Thus, understanding the relationships between drug chemical structure, dosing regimen, and organ penetration is crucial to the development of new and effective drug therapies. Motivated by this, the long-term goal of this program is to establish a measurement standard of molecular transport parameters affecting the passage of therapeutic agents across biological barriers in vivo. Specifically, the objective of this proposal is to demonstrate that electrochemical, aptamer-based (E-AB) sensors – an emerging sensing platform with the ability to continuously measure the levels of specific molecules in the body – can support continuous monitoring of molecular transport from blood to liver, prostate and brain. The proposed measurements will determine the transport parameters of seven therapeutic agents (three aminoglycoside, three β-lactam and one glycopeptide antibiotics) across four biological barriers (i.e., blood-liver, blood-prostate, blood-brain and blood-cerebrospinal fluid). These drugs were chosen because, although effective at treating infections across organ barriers, they cause dangerous side effects driven by their narrow therapeutic window, making their precise dosing an important medical challenge. The central hypothesis of this work is that achieving spatially and temporally resolved drug measurements in blood and target organs will produce unprecedented permeability data that will guide new therapeutic drug development toward the creation of permeability-enhanced therapeutics and more effective dosing regimens. This hypothesis will be tested by pursuing three specific aims: 1) Determine the kinetics of drug uptake in the liver via continuous, seconds-resolved E-AB measurements; 2) Determine the transport kinetics of antibiotics through the prostatic barrier; and 3) Determine the transport kinetics of prophylaxis antibiotics delivered from blood to the brain. The proposed research is significant because it will define the structural and transport characteristics necessary for therapeutic agents to penetrate targeted organs and propel the study of other therapeutics beyond the families of antibiotics considered here. Thus, this work will develop foundational knowledge and generate the necessary resources for other researchers and industries – working on drug development, in-vivo testing and clinical dose scaling – to advance the field of therapeutics. The proposed research will have an immediate positive impact as it will establish a better understanding of therapeutic drug transport within compartments in the body. Longer term, this work will have established the groundwork necessary for the in-vivo evaluation of molecular transport across tight biological barriers.

项目摘要 治疗药物进入特定器官的能力很大程度上取决于血液组织的性质 所说器官的障碍。例如，前列腺和大脑具有没有细胞间间隙的紧密障碍， 大多数药物无法在足够高的水平上渗透到热有效。那，理解 药物化学结构，给药方案和器官穿透之间的关系对 开发新的有效药物疗法。由此激励，该计划的长期目标 是建立影响治疗通过的分子传输参数的测量标准 体内生物屏障的代理。具体而言，该提议的目的是证明 电化学，基于APATMER（E-AB）传感器 - 一个具有继续的能力的新兴传感平台 测量体内特定分子的水平 - 可以支持分子转运的连续监测 从血到肝脏，前列腺和大脑。提出的测量将确定 七种治疗剂（三种氨基糖苷，三种β-内酰胺和一种糖肽抗生素） 生物屏障（即血液，血液左右，血脑和血红脊髓液）。这些药物是 之所以选择，是因为尽管有效地治疗跨器官屏障的感染，但它们会引起危险的一面 效果由狭窄的治疗窗口驱动，使其确切的给药是一个重要的医疗挑战。 这项工作的中心假设是在空间和暂时解决的药物测量中实现 血液和目标器官将产生前所未有的渗透率数据，以指导新的治疗药物 发展渗透性增强疗法和更有效的给药方案的发展。 该假设将通过追求三个具体目的来检验：1）确定药物吸收动力学 肝脏通过连续分辨的E-AB测量值； 2）确定抗生素的运输动力学 通过前列腺障碍； 3）确定从 向大脑血液。拟议的研究很重要，因为它将定义结构和运输 治疗剂要穿透目标器官并推动其他其他的研究所必需的特征 此处考虑的抗生素家族以外的治疗剂。那将发展这项工作 知识并为其他研究人员和行业创造必要的资源 - 从事毒品的工作 发育，体内测试和临床剂量缩放 - 以推进治疗领域。提议 研究将立即产生积极的影响，因为它将更好地了解治疗药物 体内隔室内的运输。从长远来看，这项工作将确定基础 体内评估分子横跨紧密生物屏障所必需的。