SBIR/STTR Award attributes
We propose to develop a novel antithrombotic agent with improved efficacy and safety over standard of care via the following properties: 1) specific targeting to procoagulant surfaces, 2) high coagulant site binding and blocking capacity, 3) potent and specific effects of reducing clot size by selectively blocking only highly coagulant sites, 4) reducing bleeding risk compared with current antiplatelet standard of care, 5) immediate onset, and 6) rapid clearance from circulation. The specific target patient cohorts include, but may not be limited to new acute thrombosis, recurrent acute thrombosis despite standard of care, thrombosis in the setting of high bleeding risk, and ischemic reperfusion injury/recurrent thrombosis after thrombectomy or thrombolysis, including acute stroke and other adverse ischemic events. Care for each of these cohorts has improved markedly in recent decades, but altogether still represents unsolved management of the critical balance of reducing clotting risk without risks of moderate to severe clinical bleeding, or in cases of clot removal, subsequent recurrent thrombosis. This represents a major unmet clinical need, which we are seeking to address. Our team has developed, patented, and thoroughly tested a synthetic, highly stable unilamellar liposome nanoparticle composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) outwardly exposing Zn(II)−bis-dipicolylamine cyanine 3 [C22,22] (abbreviated, DPA-Cy3[22,22]; together, DPAL for DPA- exposing liposome nanoparticles), designed and demonstrated by us to bind specifically the procoagulant phospholipid phosphatidylserine (PS) on the membranes of highly activated procoagulant platelets, extracellular vesicles, and other procoagulant PS+ cellular membranes. We seek specifically to target patient cohorts for which antithrombotics present high risk of bleeding, or are insufficient in preventing thrombosis, as outlined above - in each of these cases, PS exposure induced by the principal adverse event directly propagates coagulation and ensuing coagulopathies which continue to present problems in clinical management. DPAL represent an innovative, specific and targeted approach to preventing or reducing risk for adverse cardiovascular events while simultaneously reducing risk of clinical bleeding compared to current antithrombotics, via selective and potent targeting of procoagulant cellular membranes. Our strong preliminary data demonstrate that DPA-exposing liposomes (DPAL) harbor the necessary properties to fulfill the translational goals. We will achieve the following Phase I milestone aims: 1) prepare and characterize DPAL, determine DPAL stability profile, and evaluate endothelial toxicity, damage and permeability; 2) optimize DPAL dosage and determine in vivo anticoagulant efficacies in acute blockade of injury- and agonist-induced thrombosis while maintaining hemostasis in mouse models. These essential studies will firmly set the stage for further translational studies moving to clinical trials.
