Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY Disseminated intravascular coagulation (DIC) is the pathophysiologic response to injury that leads to the formation of microthrombi and subsequent activation of fibrinolysis. DIC is characterized by the consumption of platelets, fibrinogen, and clotting factors, and it can present clinically with prothrombotic and/or hemorrhagic phenotypes. DIC is most commonly caused by sepsis but can also be caused by trauma, cancer, pregnancy, or severe organ injury. The treatment approach for DIC involves addressing the underlying cause, but the contradictory nature of the disorder makes identifying an effective treatment protocol challenging, which is reflected in the high mortality rate (50%) for humans with sepsis-induced DIC. DIC does not only affect humans however, and the mortality for dogs with DIC is even higher at 62.5%. The benefits of anticoagulants and fibrinolytics are still being studied but have been associated with an increased risk of off-target bleeding. We have developed fibrin-specific nanogels (FSNs), which we have used in vivo to site-specifically deliver anti- clotting drugs while also enhancing fibrin cross-linking and clot formation. Preliminary data have shown that anticoagulant- or fibrinolytic-loaded FSNs address both DIC phenotypes by targeting and dissolving existing clots, while simultaneously promoting clotting at sites of bleeding. Notably, the drug-loaded FSNs improve hemostasis within only thirty minutes. When dual-loaded with both fibrinolytic tissue plasminogen activator (tPA) and anticoagulant antithrombin-3 (AT3), FSNs have the potential to provide an enhanced effect by acting on two different mechanisms. The objective of this proposal is to establish anticoagulant- and fibrinolytic-loaded FSNs as safe and effective adjuvant therapies for sepsis-induced DIC and to further understand the mechanisms by which loaded FSNs rapidly improve DIC outcomes. It is expected that dual-loaded FSNs will result in better DIC outcomes than tPA and AT3 administered systemically or individually in FSNs by interacting directly with neutrophils to recover platelet count and reduce hemorrhage. Aim 1 will optimize FSN drug-loading by examining different loading doses of tPA and AT3 in FSNs and assessing their stability, loading efficiencies, release profiles, and clotting and fibrinolytic abilities. Aim 2 will optimize the dose of loaded FSNs in vivo by examining biodistribution, coagulation, microthrombi development, and side effects. Aim 3 will assess the role of neutrophils in rapidly rescuing platelet counts with in vitro and in vivo models treated with drug-loaded FSNs. The successful completion of these aims will identify the pathophysiology behind targeted tPA and AT3 treatment and provide the framework for moving this novel DIC therapy into clinical trials. This proposal and associated mentorship team will provide training critical for the applicant’s development as an independent clinician-scientist developing drug delivery platforms for cardiovascular diseases that affect both humans and animals. The training environment at North Carolina State University is ideal for the applicant’s interdisciplinary training goals, as the applicant also has access to resources and opportunities at Duke University and UNC-Chapel Hill.
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