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