In-Vivo Monitoring of Therapeutic Drug Transport Across Biological Barriers

项目摘要 治疗药物进入特定器官的能力在很大程度上取决于血液组织的性质 这些器官的屏障。例如，前列腺和大脑有紧密的屏障，没有细胞间的间隙， 大多数药物不能以治疗有效的足够高的水平渗透它们。因此，理解 药物化学结构、给药方案和器官渗透之间的关系对于 开发新的有效的药物疗法。受此启发，该计划的长期目标 建立影响药物通过的分子转运参数的测量标准 药物在体内穿过生物屏障。具体而言，本提案的目的是表明， 电化学，基于适体（E-AB）的传感器-一种新兴的传感平台，能够连续 测量体内特定分子的水平-可以支持对分子运输的持续监测 从血液到肝脏前列腺和大脑建议的测量将确定的运输参数 七种治疗药物（三种氨基糖苷类、三种β-内酰胺类和一种糖肽类抗生素）， 生物屏障（即，血-肝、血-前列腺、血-脑和血-脑脊液）。这些药物 之所以选择它，是因为尽管它能有效治疗跨越器官屏障的感染， 由于其狭窄的治疗窗口，使其精确给药成为一项重要的医学挑战。 这项工作的中心假设是，实现空间和时间分辨的药物测量， 血液和靶器官将产生前所未有的渗透性数据， 因此，本领域的技术人员将致力于开发渗透性增强的治疗剂和更有效的给药方案。 将通过追求三个具体目标来测试该假设：1）确定在小鼠中药物摄取的动力学。 通过连续的、秒分辨的E-AB测量肝脏; 2）确定抗生素的转运动力学 通过前列腺屏障;和3）确定从前列腺屏障递送的预防性抗生素的转运动力学。 血液进入大脑。拟议的研究是重要的，因为它将定义结构和运输 治疗剂渗透靶器官并推动其他靶器官的研究所必需的特征 抗生素家族之外的治疗方法。因此，这项工作将发展基础 知识和产生必要的资源，为其他研究人员和行业-工作的药物 开发、体内测试和临床剂量缩放-推进治疗领域。拟议 研究将产生直接的积极影响，因为它将建立对治疗药物的更好理解， 在体内的隔室中运输。从长远来看，这项工作将奠定基础 这是体内评价分子穿过紧密生物屏障转运所必需的。

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.