A Nitric Oxide-Releasing Heparin Conjugate for Delivery of a Combined Antiplatelet/Anticoagulant Agent
Open accessAbstract
Heparin is a widely used anticoagulant due to its ability to inhibit key components in the coagulation cascade such as Factor Xa and thrombin (Factor IIa). Its potential to preferentially bind to antithrombin (ATIII) results in a conformational change and activation that leads to the prevention of fibrin formation from fibrinogen and ultimately obstructs a hemostatic plug from forming. Nitric oxide (NO) exhibits potent antiplatelet activity attributed to its capacity to increase the amount of cyclic guanosine monophosphate (cGMP) within platelets, which decreases the Ca2+ concentration required for platelet activation. Currently there is no single agent that combines the functions of both antiplatelet and anticoagulant (anti-Xa and anti-IIa) activities to effectively block both the extrinsic and the intrinsic coagulation pathways. The research reported herein demonstrates the ability to combine the physiological capabilities of both heparin and NO into one functional compound via use of a spermine derivative of heparin, thus enabling formation of a novel diazeniumdiolate (NONOate). The heparin–spermine NONOate has a half-life of 85 min at 25 °C (pH 7.4). The heparin backbone of the conjugate maintains its anticoagulant activity as demonstrated via an anti-Xa assay, providing an anticoagulant conversion of 3.6 μg/mL of the heparin–spermine–NONO conjugate being equivalent to 2.5 μg/mL (0.50 IU/mL) of underivatized heparin in terms of anti-Xa activity. Using standard platelet aggregometry, it is shown that the functionality of the NO release portion of the heparin conjugate prevents (nearly 100%) platelet aggregation in the presence of adenosine diphosphate (ADP, platelet agonist).
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cGMP increases cAMP indirectly through phosphodiesterase III, decreasing intracellular calcium.
“In addition, the cGMP increases cyclic adenosine monophosphate (cAMP) levels indirectly through phosphodiesterase III, which will also decrease the intracellular calcium concentration.”
From Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO) (2016) · cites this paper as [126]
NO-activated sGC reduces intracellular calcium, inhibits platelet PI3-kinase, and reduces affinity and number of fibrinogen binding sites on GPIIb/IIIa.
“The NO activated sGC ultimately results in reduced intracellular calcium, inhibition of platelet phosphoinositide 3-kinase (PI3), and reduced affinity as well as number of surface membrane fibrinogen binding sites on platelets (GPIIb/IIIa).117,121–126”
From Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO) (2016) · cites this paper as [126]
Encapsulating N-diazeniumdiolates within pH- or thermo-sensitive liposomes achieves controlled release; pH or temperature fluctuations change proton influx through the biolayer membrane and induce significant NO release.
“Other researchers have conducted further studies to encapsulate NO donors within pH126 or thermo-sensitive247 liposomes to achieve controlled release. In short, when N-diazeniumdiolates are encapsulated within liposomes, pH or temperature fluctuations change the proton influx through the biolayer membrane and subsequently induce a significant NO release.”
From Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO) (2016) · cites this paper as [126]
Considerable effort has been devoted to developing combination therapy and hybrid drugs that combine NO release functionality with other active agents for increased efficacies, including anticoagulants, direct thrombin inhibitors, antimicrobial metal ions, quaternary ammonium compounds, PEG, antibiotics, and NSAIDs.
“Recently, considerable effort has been devoted to develop combination therapy and hybrid drugs that combine NO release functionality with other active agents for increased efficacies, including anticoagulants,35,126 direct thrombin inhibitors,36,43 antimicrobial metal ions,215 quaternary ammonium compounds,70 PEG,115 antibiotics,296 and non-steroidal anti-inflammatory drugs (NSAIDs), such as ibu”
From Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO) (2016) · cites this paper as [126]
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Cited by
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Wo, Y., Brisbois, E. J., Bartlett, R. H., & Meyerhoff, M. E. (2016) · Biomaterials Science · doi:10.1039/c6bm00271d · Cited by 251 · see citing works
Self-citationWo, Y., Li, Z., Brisbois, E. J., Colletta, A., Wu, J., Major, T. C., Xi, C., Bartlett, R. H., Matzger, A. J., & Meyerhoff, M. E. (2015) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.5b07501 · Cited by 128 · see citing works
Self-citation
- Authors
- Suchyta, D. J., Handa, H., & Meyerhoff, M. E.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Meyerhoff, Mark E.
- Venue
- Molecular Pharmaceutics
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-01-14
- Volume
- 11
- Issue
- 2
- Pages
- 645-650
- ISSN
- 1543-8384 (ISSN-L)
- 1543-8392
- PMC
- PMC3993940
- OpenAlex
- W2328706562
- Cited by
- 40
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 8 · 2020: 4 · 2019: 2 · 2017: 4 · 2016: 4 · 2015: 1
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Pharmaceutics (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (K25HL111213)
- National Institute of Biomedical Imaging and Bioengineering (EB-000783, R01EB000783)
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- heparin, nitric oxide, diazeniumdiolates, NONOates, spermine, antiplatelet activity, anticoagulant activity, factor Xa inhibition, thrombin inhibition, antithrombin III, platelet aggregation, ADP, cyclic GMP, drug delivery
- MeSH terms
- Anticoagulants, Heparin, Nitric Oxide, Platelet Aggregation, Platelet Aggregation Inhibitors, Spermine, Molecular Structure
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