Aptamer-Hydrogel Hybrid Sensors for Continuous Therapeutic Drug Monitoring

 描述：这项建议的目标是开发能够提供连续实时治疗药物监测的电化学生物传感器，具有前所未有的化学特异性和时间分辨率。提供有关个人对疗法反应的实时信息的能力，有可能通过提供个性化治疗来彻底改变医疗保健。治疗窗口狭窄的药物如果剂量过大或不足，就会变得有毒或无效。保持最有效的剂量，根据患者的个性化，可以减少毒性，最大限度地发挥治疗效果，最终改善患者的预后。不幸的是，目前监测治疗的方法很繁琐(需要几十分钟到几个小时)，而且执行时不在医疗点，排除了实时反馈。生物传感器代表着一种很有前途的替代方案，但在生物样品基质中受到挑战时，往往无法对特定的目标做出反应。这一故障是生物污垢的结果，它掩盖了真正的传感器响应。在这里，我们的目标是利用最先进的生物分析科学和生物兼容材料(水凝胶)工程来开发能够在体内实时连续监测治疗药物的混合传感器。其具体目标是将水凝胶膜的生物兼容性与基于适体(E-AB)的电化学传感器的快速、选择性和特异性识别能力结合起来。该提案的目的是首先建立基本和通用的传感器设计和生物材料工程指南，然后将传感器转化为用于多分析物检测的商业工程体内探针。短期目标是开发用于实时监测用于治疗囊性纤维化肺恶化的抗生素妥布霉素的传感器。从长远来看，结合PI的传感器开发专业知识和Co-PI的生物材料工程专业知识，这里开发的通用传感器将适用于与包括组织和神经系统在内的各种生物界面进行接口。

 DESCRIPTION: The objective of this proposal is to develop electrochemical biosensors capable of providing continuous real-time therapeutic drug monitoring with unprecedented chemical specificity and temporal resolution. The ability to provide real-time information about an individual's response to therapeutics has the potential to revolutionize healthcare by offering personalized treatment. Drugs with narrow therapeutic windows become toxic or ineffective if over- or under-dosed. Maintaining the most efficient dosage, personalized to the patient, can reduce toxicity, maximize efficacy of treatment, and ultimately improve patient outcome. Unfortunately, current methodologies for monitoring therapeutics are cumbersome (requiring tens of minutes to hours) and are performed removed from the point of care precluding real-time feedback. Biosensors represent a promising alternative but often fail to respond to specific targets when challenged in biological sample matrices. This failure is a result of biofouling, which masks the true sensor response. Here, we aim to leverage state-of-the-art bioanalytical science with biocompatible material (hydrogel) engineering to develop hybrid sensors capable of real-time continuous therapeutic drug monitoring in vivo. The specific goal is to couple the biocompatibility of hydrogel membranes with the rapid, selective, and specific recognition capabilities of electrochemical, aptamer-based (E-AB) sensors. The aims of the proposal are to first establish fundamental and universal sensor design and biomaterial engineering guidelines followed by the translation of the sensor to commercially engineered in vivo probes for multi- analyte detection. The short-term goal is to develop sensors for the real-time monitoring of the antibiotic tobramycin used for treatment of cystic fibrosis pulmonary exacerbations. In the long-term, combining the sensor development expertise of the PI and the biomaterial engineering expertise of the Co-PI, the general sensors developed here will be adapted to interface with a variety of biological interfaces including tissue and neuronal systems.