Antibacterial and Antithrombotic Catheter Lock Solutions Based on Controlled Release of Nitric Oxide

总结 中心静脉导管是现代临床实践中不可或缺的工具，为患者提供静脉通路。 血液透析、化疗、肠外营养和重复采血。然而，它们具有高风险 感染和血栓形成，导致发病率、死亡率和住院时间增加。频繁 使用抗生素和抗凝剂预防和治疗这些并发症会导致细菌耐药性， 不良副作用如出血。因此，迫切需要新的战略，以减少 与中心静脉导管相关的感染和血栓形成并发症。该项目旨在打击 这些并发症使用释放一氧化氮（NO）的封管液，一种同时发挥这两种作用的天然药物 杀菌和抗血栓形成活性，而不产生耐药性和副作用。锁 溶液含有S-亚硝基谷胱甘肽作为天然无毒的NO供体。NO的精确控制释放 是通过我们的创新配方实现的，该配方基于主体-客体包合物的形成， S-亚硝基谷胱甘肽的两性离子形式和S-亚硝基谷胱甘肽纳米晶体的悬浮液的产生。 NO释放的持续时间可从1天到1个月以上调整，以满足锁定方案的要求 在不同的导管应用中。将NO的排放量控制在安全有效的范围内，达到抑菌的目的 和血栓生长而不引起对组织和血液的毒性。由于NO通过膜的高扩散率， 血管内导管的聚合物壁，它不仅在管腔内空间和远端导管中产生 开口，但也从导管和毂的外表面释放。与其他锁解决方案相比 使用传统的抗菌剂或抗凝剂，NO释放解决方案是独一无二的，因为它完全保护了 防止细菌定植和血栓形成。 在目标1中，我们将设计各种S-亚硝基谷胱甘肽制剂，以提供短期，中期和长期的治疗。 由硅橡胶或聚氨酯制成的市售中心静脉导管的术语NO释放。在目标2中， NO释放封闭溶液对嗜酸性细菌和生物膜细菌的体外抗微生物活性将 使用五种流行的血液传播微生物进行测试，包括一种多重耐药菌株。潜在的溶解活性， 将在体外评价红细胞和对内皮细胞的毒性。在目标3中，抗血栓形成疗效 短期和中期NO释放封闭溶液将在7天的猪实验中评估。锁定 协议将模拟血液透析和化疗中的锁定频率。在目标4中， 猪模型将用于比较具有3天、1周和4周的NO释放的溶液与牛磺罗定。 柠檬酸盐-肝素封管液，用于感染和血栓形成。该项目的成功将导致 新一代廉价的锁定解决方案，将大大降低感染和血栓形成的风险， 中心静脉导管

SUMMARY Central venous catheters are an indispensable tool in modern clinical practice to provide venous access for hemodialysis, chemotherapy, parenteral nutrition, and repeated blood sampling. However, they carry a high risk of infection and thrombosis, leading to increased morbidity, mortality, and length of hospital stay. The frequent use of antibiotics and anticoagulants to prevent and treat these complications causes bacterial resistance and adverse side effects such as bleeding. Therefore, there is a pressing need for novel strategies to reduce infectious and thrombotic complications associated with central venous catheters. This project aims to combat these complications using catheter lock solutions that release nitric oxide (NO), a natural drug exerting both bactericidal and antithrombogenic activities without engendering drug resistance and side effects. The lock solution contains S-nitrosoglutathione as a natural and non-toxic NO donor. Precisely controlled release of NO is achieved by our innovative formulations based on the formation of host-guest inclusion complexes with the zwitterionic form of S-nitrosoglutathione and the creation of suspensions of S-nitrosoglutathione nanocrystals. The duration of NO release is tunable from 1 day to over 1 month to meet the requirements of locking regimens in different catheter applications. The flux of NO is controlled within the safe and effective range to inhibit bacteria and thrombus growth without causing toxicity to tissue and blood. Due to the high diffusivity of NO through the polymer walls of intravascular catheters, it is not only generated in the intraluminal space and distal catheter opening, but also released from the exterior surface of the catheter and the hub. Compared to other lock solutions using traditional antimicrobials or anticoagulants, the NO release solution is unique due to its full protection over the entire catheter from both bacterial colonization and thrombus formation. In Aim 1, we will design various S-nitrosoglutathione formulations to provide short-term, medium-term, and long- term NO release from commercial central venous catheters made of silicone rubber or polyurethane. In Aim 2, the in vitro antimicrobial activity of the NO release lock solution against planktonic and biofilm bacteria will be tested using five prevalent bloodborne microbes including a multidrug-resistant strain. Potential lytic activity to erythrocytes and toxicity to endothelial cells will be evaluated in vitro. In Aim 3, the antithrombotic efficacy of short-term and medium-term NO release lock solutions will be assessed in 7-day pig experiments. The locking protocols will simulate the locking frequencies in hemodialysis and chemotherapy. In Aim 4, a 4-week chronic pig model will be used to compare solutions with 3 days, 1 week, and 4 weeks of NO release with taurolidine- citrate-heparin lock solutions with regard to both infection and thrombosis. Success of this project would lead to a new generation of inexpensive lock solutions that will dramatically reduce infectious and thrombotic risks of central venous catheters.