Local Anesthetic Cardiotoxicity: Nanotechnology Therapy

描述（由申请人提供）：局部麻醉剂（LAs）通过电压、时间和频率依赖性地阻断钠通道电导（I-Na），可逆地阻止神经中的脉冲传递。这些药理作用是在临床护理中使用LAs的基础，为接受外科手术或分娩的患者提供区域麻醉（例如硬膜外阻滞）。然而，无意的血管内注射或过量可能导致其他组织（如心脏、中枢神经系统）出现不希望的INa阻断，从而导致潜在的危及生命的不良事件（如心脏骤停、癫痫发作）。虽然LA过量引起的癫痫发作活动和呼吸抑制可能危及生命，但这些事件可以分别通过抗癫痫药物和受控人工通气轻松治疗。同样重要或更重要的是，目前存在一些治疗血管内注射引起的心脏毒性的选择（例如ACLS）。由于这些原因，一种能够快速有效地治疗LA毒性心脏效应的药物或技术将是有用的。这项拨款的目的是产生必要的知识，以创造专门设计用于治疗遭受LAs毒性作用的患者的药物。粒子科学工程的最新进展为开发旨在成功治疗药物中毒的高效治疗策略提供了新的和令人兴奋的机会。具体来说，纳米技术的出现及其解决主要生物医学问题的巨大潜力现在为解决LA毒性问题提供了无与伦比的机会。美国国家科学基金会粒子科学与技术工程研究中心的同事将合成四种直径为10-100 nm的生物相容性和可生物降解纳米颗粒（NPs），用于LAs的解毒。这些NPs将依靠吸收（微乳液）、吸附（电子受体）或两种机制（2种“智能”微乳液）来降低各种介质中LA的自由浓度，并降低LA在组织和完整生物体中的生物效应。研究NPs的目的是：1)详细描述NP-LA相互作用的物理化学特征（目的A）； 2)确定生物系统中NPs是否可以减弱LAs的心脏毒性作用（目的B）。这个高度跨学科的项目跨越有机化学、工程和医学，包含两个目标和三个具体目标：具体目标#1：确定NPs从简单（生理盐水）和复杂（人血浆和血液）介质中去除LAs的提取效率。优化各种NPs的LA萃取效率。特定目标#2：确定不同类型的NPs可以有效提取LAs的分子机制。特定目标#3：确定纳米颗粒在三个功能水平上减轻或逆转LAs的心脏毒性作用的有效性：1)单细胞（心室肌细胞），2)组织（分离的心脏）和3)完整的大鼠（闭合的胸部）。

DESCRIPTION (provided by applicant): Local anesthetics (LAs) reversibly prevent impulse transmission in nerves by voltage-, time- and frequency-dependent blockade of sodium channel conductance (I-Na). These pharmacological actions underlie the therapeutic use of LAs in clinical care to provide regional anesthesia (e.g., epidural blockade) for patients undergoing surgical procedures or childbirth. However, inadvertent intravascular injection or overdose may lead to undesired INa blockade in other tissues (e.g., heart, central nervous system) and thereby cause potentially life threatening adverse events (e.g., cardiac arrest, seizures). Although seizure activity and respiratory depression caused by LA overdose are potentially life threatening, these events can be readily treated with antiepileptic medications and controlled artificial ventilation, respectively. Of equal or greater importance, few options (e.g., ACLS) currently exist for treatment of cardiac toxicity caused by intravascular injection. For these reasons, an agent or technique allowing rapid, efficacious treatment of the cardiac effects of LA toxicity would be useful. The objectives of this grant are to generate the knowledge necessary to create agents specifically designed to treat patients suffering from the toxic effects of LAs. Recent advances in particle science engineering now afford new and exciting opportunities to develop highly effective therapeutic strategies aimed at successfully treating drug poisonings. Specifically, the recent advent of nanotechnology with its tremendous potential to solve major biomedical problems now offers unparalleled opportunities to solve the problem of LA toxicity. Four types of biocompatible and biodegradable nanoparticles (NPs) with 10-100 nm diameter will be synthesized by colleagues in the NSF Engineering Research Center for Particle Science and Technology for detoxification of LAs. These NPs will rely on absorption (microemulsions), adsorption (electron acceptor), or both mechanisms (2 types of "smart" microemulsions) to reduce the free concentration of LA in various media and decrease the biological effects of LA in tissues and intact organisms. The NPs will be studied to 1) detail the physicochemical characterization of the NP-LA interaction (Objective A), and 2) determine whether the cardiotoxic effects of LAs can be attenuated by NPs in biological systems (Objective B). This highly multidisciplinary project spanning organic chemistry, engineering, and medicine contains two objectives and three specific aims: Specific Aim #1: Determine the extraction efficiency of NPs to remove LAs from simple (normal saline) and complex (human plasma and blood) media. Optimize LA extraction efficiency of the various NPs. Specific Aim #2: Determine the molecular mechanisms whereby the different types of NPs can efficiently extract LAs. Specific Aim #3: Determine the effectiveness of nanoparticles to attenuate or reverse the cardiotoxic effects of LAs at three functional levels: 1) single cell (ventricular myocytes), 2) tissue (isolated hearts), and 3) intact rat (closed chest).