SanguiStop: Intravenous Nanomedicine for Targeted Thrombin Delivery in Hemorrhage Control
Abstract
Topic Area Relevance: The project proposal is responsive to the Topic Area of Hemorrhage Control. The proposal focuses on developing an intravenously administrable therapeutic technology that delivers an enzyme, thrombin, directly to the site of bleeding injury to enhance the formation of a biological polymer, fibrin, that is essential for rapid formation of robust and stable clots to stop bleeding (a process called hemostasis). Generation of thrombin and corresponding formation of fibrin for sable hemostatic clots can be drastically impaired in severe traumatic injury and hemorrhage, due to bleeding-associated loss of blood cells called platelets, as well as loss of plasma clotting factors. The gold standard to restore these capabilities is transfusion of donor platelets and plasma into the bleeding patient as early as possible after injury, but timely and sufficient availability of such transfusions is extremely challenging in austere battlefield conditions. This logistical challenge leads to a significant number of morbidities and mortalities in our injured Warfighters, which could be potentially prevented if effective bleeding control technologies were readily available on demand. The Department of Defense (DOD) is currently conducting robust efforts to improve on-field blood product transfusion availability via research and development of cold-stored, freeze-dried and cryopreserved blood products. However, since all blood products are currently donor-dependent and there is a persistent shortage of blood donors, there is a need for alternative intravenous approaches that could serve as surrogate or bridge technologies for bleeding control to save lives. Such technologies can become complementary as well as adjunctive approaches when natural blood products are of limited availability. SanguiStop is envisioned to be such a technology. SanguiStop is a lipid-based nanoparticle (LNP) that can be loaded with thrombin and decorated on the surface with molecular motifs that specifically bind to proteins that are exposed uniquely at bleeding injury site. The design is inspired by blood platelets that are the primary players in orchestrating clot formation to stop bleeding. Specifically, platelets can: (1) home in rapidly to a bleeding injury site, (2) accumulate by binding to specific proteins uniquely exposed at the site, and (3) through a complex concert of biological reactions among clotting factors assembled on the platelet surface (collectively called coagulation complex formation) amplify thrombin generation locally, to enable rapid fibrin formation for hemostasis. SanguiStop LNPs are essentially designed to perform in a similar way where they home in and bind to specific proteins exposed at the injury site, but instead of prompting complex coagulation reactions to make thrombin, they actually directly carry and release thrombin at the site. This allows SanguiStop LNPs to circumvent any potential depletion or dysfunction issues that may exist with the bleeding patient’s native platelets and clotting factors (often a hallmark of severe trauma), and work directly to make fibrin locally at the bleeding injury site to potentially stop hemorrhage. Since the technology is nanoparticle based that can be potentially freeze-dried into a small carry volume aqueous-reconstitutable powder, it can enable field-deployability and portability for hemorrhage control applications at point of injury (POI) as well as en route and prolonged care. We envision that SanguiStop can significantly transform survival outcomes in both military and civilian settings and potentially advance our goal of achieving zero preventable deaths from traumatic hemorrhage. Overview of Proposed Research: The central research hypothesis is: A lipid nanoparticle system that can be loaded with thrombin and surface-decorated with combination of ligands that bind von Willebrand Factor (vWF) and collagen can specifically adhere/aggregate at the vascular injury site a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210426
Entities
People
- Anirban Sen Gupta
Organizations
- Case Western Reserve University
- United States Army