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

基于一氧化氮控制释放的抗菌和抗血栓导管锁解决方案

• 批准号: 10634183
• 负责人: Xuewei Wang
• 金额: $ 35.32万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634183
• 关键词: Adoption; Animal Experiments; Animal Testing; Anti-Bacterial Agents; Antibiotics; Anticoagulants; Bacteria; Blood; Blood specimen; Catheters; Cells; Chemistry; Chronic; Citrates; Complex; Cyclodextrins; Data; Diffuse; Distal; Drug resistance; Drug usage; Endothelial Cells; Erythrocytes; Ethanol; Exhibits; Family suidae; Formulation; Frequencies; Gases; Generations; Growth; Hemodialysis; Hemorrhage; Heparin; Human body; In Vitro; Infection; Kinetics; Legal patent; Length of Stay; Liquid substance; Lytic; Metals; Microbe; Microbial Biofilms; Modernization; Morbidity - disease rate; Multi-Drug Resistance; Nitric Oxide; Nitric Oxide Donors; Parenteral Nutrition; Permeability; Pharmaceutical Preparations; Physiological; Polymers; Polyurethanes; Prevention; Procedures; Prodrugs; Property; Propylene Glycols; Protocols documentation; Regimen; Risk; S-Nitrosoglutathione; S-Nitrosothiols; Safety; Saline; Silicone Elastomers; Solubility; Solvents; Surface; Suspensions; Testing; Thrombosis; Thrombus; Time; Tissues; Toxic effect; Venous; antimicrobial; antimicrobial drug; aqueous; bacterial resistance; bactericide; chemotherapy; clinical application; clinical practice; combat; controlled release; cytotoxicity; design; diazeniumdiolate; experimental study; high risk; hydrophilicity; in vitro testing; infection risk; innovation; mortality; nano; nanocrystal; novel strategies; pathogen; porcine model; prevent; resistant strain; side effect; success; thrombogenesis; thrombotic; thrombotic complications; tool

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.

概括 中央静脉导管是现代临床实践中必不可少的工具，可为 血液透析，化学疗法，肠胃外营养和反复采样。但是，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来预防和治疗这些并发症会引起细菌耐药性和 不良副作用，例如出血。因此，有必要采取新颖的策略来减少 与中央静脉导管相关的传染性和血栓形成并发症。该项目旨在作战 这些并发症使用释放一氧化氮（NO）的导管锁溶液，一种天然药物，两者都施加 杀菌性和甲状化活性，无产生耐药性和副作用。锁 溶液包含S-硝基谷硫硫代作为天然和无毒的无供体。精确控制否 是通过我们的创新配方来实现的，基于与 s-硝基谷硫硫代硫酸盐的zwittionic形式，并创建了s-硝基谷胱甘肽纳米晶体的悬浮液。 无释放的持续时间可以调整为1天到1个月以上，以满足锁定方案的要求 在不同的导管应用中。 NO的通量在安全有效的范围内受到控制以抑制细菌 和血栓生长而不会引起对组织和血液的毒性。由于NO的高扩散率 血管内导管的聚合物壁不仅在腔内空间和远端导管中产生 开口，但也从导管和轮毂的外表面释放。与其他锁定解决方案相比 使用传统的抗菌药物或抗凝剂，NO释放解决方案是独一无二的 来自细菌定植和血栓形成的整个导管。 在AIM 1中，我们将设计各种S-硝基谷二硫代硫酸含硫酸硫硫代硫酸盐制剂，以提供短期，中期和长期 术语不从硅胶橡胶或聚氨酯制成的商用中央静脉导管释放。在AIM 2中， 无释放锁定溶液针对浮游物和生物膜细菌的体外抗菌活性将是 使用五个普遍的血源微生物（包括多药耐药菌株）进行了测试。潜在的裂解活性 红细胞和对内皮细胞的毒性将在体外评估。在AIM 3中，抗强制性功效 短期和中期无释放锁解决方案将在7天的猪实验中评估。锁定 方案将模拟血液透析和化学疗法中的锁定频率。在AIM 4中，为期4周的慢性 猪模型将用于比较3天，1周和4周无释放的解决方案 - 关于感染和血栓形成，柠檬酸甲酸盐链蛋白锁解决方案。这个项目的成功将导致 新一代廉价的锁解决方案将大大降低感染性和血栓形成风险 中央静脉导管。