Collaborative Research: Rapid Biosensing of Protein-Bound Drug Concentrations in the Body for Improved Drug Efficacy and Safety

精准医学旨在以最大限度地提高疗效同时最大限度地减少副作用的方式优化每个人的药物剂量。然而，在实践中，抽血的繁琐和侵入性以及随后的实验室分析的劳动密集型性质已经排除了给药的个性化。面对这种情况，临床医生基于间接的，因此通常非常不准确的体内药物浓度估计值来决定剂量，导致不希望的副作用和每年5000亿美元的医疗保健系统额外成本。鉴于此，存在对支持在护理点方便和准确地测量药物浓度的技术的主要需求，如果这种技术可以由患者在家中或工作中使用，则具有甚至更大的价值。 然而，执行药物浓度的快速测量可能是复杂的，因为大多数药物的很大一部分与血液蛋白结合。 该项目提出了一种基于适体的生化传感器，能够对蛋白质结合和未结合的药物浓度进行快速的即时测量，用于个性化医疗。这项工作包括一个综合教育计划，涉及本科生研究合作的参与，重点是代表性不足的群体。该提案的技术目标是设计和制造生化传感器设备，可以快速测量血液循环中药物的活性（未结合）和总浓度（未结合+蛋白结合）。所提出的研究是基于这样的假设，即微流体装置可以快速地对血液和间质液等生物流体进行采样，并有效地使药物的结合蛋白变性，使得未结合和总（未结合+蛋白结合）药物浓度都可以通过定量电化学适体传感器来测量。 这将通过实施一种新的膜来实现，该膜保护药物检测传感器免受释放蛋白质结合药物所需的苛刻条件的影响。 具体地，膜将对药物是可渗透的，但对从蛋白质释放药物所需的酸和碱是不可渗透的，否则这将损害传感器。 该提案旨在推进跨膜物理学的知识，酸，碱和盐条件对传感器的影响，并揭示与体内蛋白质结合的药物的百分比。 了解多少药物与蛋白质结合将导致对血液中提供治疗效果以及引起毒性或不希望的副作用的药物的未结合部分的基本知识。该技术将提供有关药物生物利用度、毒性、干扰、代谢、清除率和吸收率的信息。 总体而言，拟议的设备将改善患者健康，并将降低医疗保健服务工作流程的复杂性。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Precision medicine aims to optimize drug dosages for each individual in a manner that maximizes efficacy while minimizing side effects. In practice, however, the cumbersome and invasive nature of blood draws, and the labor-intensive nature of their subsequent laboratory analysis has precluded the personalization of dosing. In the face of this, clinicians base dosing decisions on indirect, and thus often highly inaccurate estimators of drug concentrations in the body, leading to undesired side effects and $500 billion in additional annual cost to the health-care system. Given this, there exists a major need for technologies supporting convenient and accurate measurement of drug concentrations at the point of care, with even greater value if such technology could be used by patients at home or work. Performing rapid measurement of drug concentrations can be complex, however, because a significant fraction of most drugs is bound to blood proteins. The project proposes an aptamer based biochemical sensor capable of performing rapid, point-of-care measurements of both protein-bound and unbound drug concentrations for personalized medicine. The work includes an integrated education plan that involves the participation of undergraduate research co-ops with a focus on underrepresented groups.The technical objective of this proposal is design and fabrication of biochemical sensor device that can rapidly measure both the active (unbound) and the total (unbound+protein bound) concentrations of drugs in blood circulation. The proposed research is based on the hypothesis that microfluidic devices can quickly sample biofluids such as blood and interstitial fluid, and efficiently denature the binding-protein for the drug such that both the unbound and total (unbound+protein-bound) drug concentrations can be measured by quantitative electrochemical aptamer sensors. This will be accomplished by implementing a novel membrane that protects the drug-detecting sensor from the harsh conditions necessary to liberate protein-bound drugs. Specifically, the membrane will be permeable to drugs but will be impermeable to acids and bases needed to release drug from proteins and which would otherwise harm the sensor. The proposal aims to advance knowledge spanning the physics of membranes, the influence of acid, base, and salt conditions on sensors, and shed new light on the percentage of drugs that are bound to proteins in the body. The understanding of how much drug is bound to proteins will lead to fundamental knowledge of the unbound portion of drug in blood that provides a therapeutic effect, as well as causes toxicity or unwanted side-effects. The technique will provide information on drug bioavailability, toxicity, interference, metabolism, clearance, and absorption rates. In general, the proposed devices will result in improved patient health and will reduce the complexity of workflow in healthcare delivery.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.