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很大程度上取决于血液组织的性质 上述器官的屏障。例如，前列腺和大脑有紧密的屏障，没有细胞间的间隙，而且 大多数药物不能在足够高的水平下渗透到具有治疗效果的水平。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 开发新的有效的药物疗法。在此推动下，该计划的长期目标是 就是建立影响药物通过的分子转运参数的测量标准 体内跨越生物屏障的药物。具体地说，这项提案的目标是证明 基于电化学适配子(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。建议的测量将确定以下传输参数 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) 生物障碍(即血-肝、血-前列腺、血-脑和血-脑脊液)。这些药物是 之所以选择它们是因为，尽管它们在治疗跨越器官屏障的感染方面有效，但它们会造成危险的一面 这些药物的疗效受治疗窗口狭窄的影响，这使得精确给药成为一个重要的医学挑战。 这项工作的中心假设是在空间和时间上实现药物测量 血液和靶器官将产生前所未有的渗透性数据，这些数据将指导新的治疗药物 朝着创造渗透性增强疗法和更有效的剂量方案的方向发展。 这一假说将通过追求三个具体目标来检验：1)确定药物在体内的摄取动力学 通过连续、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；以及3)确定预防性抗生素从 血液流入大脑。拟议的研究具有重要意义，因为它将定义结构和运输 治疗剂穿透靶器官并推动其他器官研究的必要特征 这里讨论的抗生素家族以外的治疗学。因此，这项工作将为今后的工作奠定基础 知识，并为其他研究人员和行业提供必要的资源--从事药物工作 开发、体内测试和临床剂量调整--推动治疗学领域的发展。建议数 研究将立即产生积极影响，因为它将建立对治疗药物的更好理解 在身体的隔间内运输。从长远来看，这项工作将奠定基础 对于在体内评估分子跨越严密的生物屏障的传输是必要的。

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.