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Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications.

Publication ,  Journal Article
Sheridan, A; Nellenbach, K; Pandit, S; Byrnes, E; Hardy, G; Lutz, H; Moiseiwitsch, N; Scull, G; Mihalko, E; Levy, JH; Brown, AC
Published in: ACS Nano
June 18, 2024

Disseminated intravascular coagulation (DIC) is a pathologic state that follows systemic injury and other diseases. Often a complication of sepsis or trauma, DIC causes coagulopathy associated with paradoxical thrombosis and hemorrhage. DIC upregulates the thrombotic pathways while simultaneously downregulating the fibrinolytic pathways that cause excessive fibrin deposition, microcirculatory thrombosis, multiorgan dysfunction, and consumptive coagulopathy with excessive bleeding. Given these opposing disease phenotypes, DIC management is challenging and includes treating the underlying disease and managing the coagulopathy. Currently, no therapies are approved for DIC. We have developed clot-targeted therapeutics that inhibit clot polymerization and activate clot fibrinolysis to manage DIC. We hypothesize that delivering both an anticoagulant and a fibrinolytic agent directly to clots will inhibit active clot polymerization while also breaking up pre-existing clots; therefore, reversing consumptive coagulopathy and restoring hemostatic balance. To test this hypothesis, we single- and dual-loaded fibrin-specific nanogels (FSNs) with antithrombinIII (ATIII) and/or tissue plasminogen activator (tPA) and evaluated their clot preventing and clot lysing abilities in vitro and in a rodent model of DIC. In vivo, single-loaded ATIII-FSNs decreased fibrin deposits in DIC organs and reduced blood loss when DIC rodents were injured. We also observed that the addition of tPA in dual-loaded ATIII-tPA-FSNs intensified the antithrombotic and fibrinolytic mechanisms, which proved advantageous for clot lysis and restoring platelet counts. However, the addition of tPA may have hindered wound healing capabilities when an injury was introduced. Our data supports the benefits of delivering both anticoagulants and fibrinolytic agents directly to clots to reduce the fibrin load and restore hemostatic balance in DIC.

Duke Scholars

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Published In

ACS Nano

DOI

EISSN

1936-086X

Publication Date

June 18, 2024

Volume

18

Issue

24

Start / End Page

15517 / 15528

Location

United States

Related Subject Headings

  • Tissue Plasminogen Activator
  • Thrombosis
  • Rats
  • Nanoscience & Nanotechnology
  • Nanogels
  • Male
  • Humans
  • Fibrinolytic Agents
  • Fibrin
  • Drug Delivery Systems
 

Citation

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Sheridan, A., Nellenbach, K., Pandit, S., Byrnes, E., Hardy, G., Lutz, H., … Brown, A. C. (2024). Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications. ACS Nano, 18(24), 15517–15528. https://doi.org/10.1021/acsnano.4c00162
Sheridan, Anastasia, Kimberly Nellenbach, Sanika Pandit, Elizabeth Byrnes, Grace Hardy, Halle Lutz, Nina Moiseiwitsch, et al. “Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications.ACS Nano 18, no. 24 (June 18, 2024): 15517–28. https://doi.org/10.1021/acsnano.4c00162.
Sheridan A, Nellenbach K, Pandit S, Byrnes E, Hardy G, Lutz H, et al. Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications. ACS Nano. 2024 Jun 18;18(24):15517–28.
Sheridan, Anastasia, et al. “Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications.ACS Nano, vol. 18, no. 24, June 2024, pp. 15517–28. Pubmed, doi:10.1021/acsnano.4c00162.
Sheridan A, Nellenbach K, Pandit S, Byrnes E, Hardy G, Lutz H, Moiseiwitsch N, Scull G, Mihalko E, Levy JH, Brown AC. Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications. ACS Nano. 2024 Jun 18;18(24):15517–15528.
Journal cover image

Published In

ACS Nano

DOI

EISSN

1936-086X

Publication Date

June 18, 2024

Volume

18

Issue

24

Start / End Page

15517 / 15528

Location

United States

Related Subject Headings

  • Tissue Plasminogen Activator
  • Thrombosis
  • Rats
  • Nanoscience & Nanotechnology
  • Nanogels
  • Male
  • Humans
  • Fibrinolytic Agents
  • Fibrin
  • Drug Delivery Systems