Thrombosis causes morbidity and mortality in many pathological conditions. Prevention by anticoagulants and anti-platelet agents and therapeutic thrombolysis by fibrinolytic plasminogen activators, PA have limited efficacy and marred by bleeding and brain injury. Our team: i) proposed that coupling to carrier red blood cells (RBC) will improve pharmacokinetics of fibrinolytic PA, permitting their preventive utility;ii) demonstrated a proof of principle for effective and safe thromboprophylaxis attained by re-infusion of RBC/tPA conjugates in animals (Nature Biotech 2003);and, iii) designed safe loading of circulating RBC by anti-RBC/tPA conjugates in vivo. In order to translate this promising prototype into clinically applicable thromboprophylaxis with clinically acceptable utility, safety and specificity, we now designed a series of anti-RBC scFv/PA fusion pro-drugs activated by thrombin. To test this platform for delivery of anti-thrombotic agents loaded on RBC carriers, we shall characterize: i) activities, pharmacokinetics and thrombin regulation of the anti-RBC scFv/PA pro-drugs (Aim 1);ii) their efficacy in mouse models of venous and arterial thrombosis (Aim 2);and, iii) safety: potential harm to RBC, bleeding, systemic effects and adverse effects in the CNS (Aim 3). Implementation of this grant will provide a basis for translation into the clinical domain of this potentially revolutionizing novel approach for safe and effective thromboprophylaxis.
we have designed a new strategy for prophylaxis of thrombosis based on coupling of fibrinolytic pro-drug recombinant fusion constructs that safely bind to carrier red blood cells (RBC). We shall characterize activities and pharmacokinetics regulation of the drugs, efficacy and safety in mouse models of thrombosis. Implementation of this translational grant will provide a solid basis for clinical development of this potentially revolutionizing novel approach for thromboprophylaxis.
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|Carnemolla, Ronald; Greineder, Colin F; Chacko, Ann-Marie et al. (2013) Platelet endothelial cell adhesion molecule targeted oxidant-resistant mutant thrombomodulin fusion protein with enhanced potency in vitro and in vivo. J Pharmacol Exp Ther 347:339-45|
|Marcos-Contreras, O A; Ganguly, K; Yamamoto, A et al. (2013) Clot penetration and retention by plasminogen activators promote fibrinolysis. Biochem Pharmacol 85:216-22|
|Zaitsev, Sergei; Kowalska, M Anna; Neyman, Michael et al. (2012) Targeting recombinant thrombomodulin fusion protein to red blood cells provides multifaceted thromboprophylaxis. Blood 119:4779-85|
|Gersh, Kathryn C; Zaitsev, Sergei; Cines, Douglas B et al. (2011) Flow-dependent channel formation in clots by an erythrocyte-bound fibrinolytic agent. Blood 117:4964-7|
|Muzykantov, Vladimir R (2010) Drug delivery by red blood cells: vascular carriers designed by mother nature. Expert Opin Drug Deliv 7:403-27|
|Zaitsev, Sergei; Spitzer, Dirk; Murciano, Juan-Carlos et al. (2010) Sustained thromboprophylaxis mediated by an RBC-targeted pro-urokinase zymogen activated at the site of clot formation. Blood 115:5241-8|
|Armstead, William M; Ganguly, Kumkum; Kiessling, J W et al. (2010) Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders. J Neurochem 113:303-12|
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