Thrombin‐inhibiting perfluorocarbon nanoparticles provide a novel strategy for the treatment and magnetic resonance imaging of acute thrombosis
Open accessAbstract
Background As a regulator of the penultimate step in the coagulation cascade, thrombin represents a principal target of direct and specific anticoagulants.Objective A potent thrombin inhibitor complexed with a colloidal nanoparticle was devised as a first-in-class anticoagulant with prolonged and highly localized therapeutic impact conferred by its multivalent thrombin-absorbing particle surface.Methods PPACK (Phe[D]-Pro-Arg-Chloromethylketone) was secured covalently to the surface of perfluorocarbon-core nanoparticle structures. PPACK and PPACK nanoparticle inhibition of thrombin were assessed in vitro via thrombin activity against a chromogenic substrate. In vivo antithrombotic activity of PPACK, heparin, non-functionalized nanoparticles and PPACK nanoparticles was assessed through intravenous (i.v.) administration prior to acute photochemical injury of the common carotid artery. Perfluorocarbon particle retention in extracted carotid arteries from injured mice was assessed via (19) F magnetic resonance spectroscopy (MRS) and imaging (MRI) at 11.7 T. Activated partial thromboplastin time (APTT) measurements determined the systemic effects of the PPACK nanoparticles at various times after injection.Results An optical assay verified that PPACK nanoparticles exceeded PPACK's intrinsic activity against thrombin. Application of an in vivo acute arterial thrombosis model demonstrated that PPACK nanoparticles outperformed both heparin (P=0.001) and uncomplexed PPACK (P = 0.0006) in inhibiting thrombosis. (19) F MRS confirmed that PPACK nanoparticles specifically bound to sites of acute thrombotic injury. APTT normalized within 20 min of PPACK nanoparticles injection.Conclusions PPACK nanoparticles present thrombin-inhibiting surfaces at sites of acutely forming thrombi that continue to manifest local clot inhibition even as systemic effects rapidly diminish and thus represent a new platform for localized control of acute thrombosis.
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Nanoparticles designed to induce acute thrombolysis of thrombotic occlusions caused by ruptured plaques are under development.
“Nanoparticles designed to induce acute thrombolysis of thrombotic occlusions caused by ruptured plaques are also under development114,115.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [114]
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Perspectives and opportunities for nanomedicine in the management of atherosclerosis
Lobatto, M. E., Fuster, V., Fayad, Z. A., & Mulder, W. J. M. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3578 · Cited by 423 · see citing works
- Authors
- MYERSON, J., HE, L., LANZA, G., TOLLEFSEN, D., & WICKLINE, S.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- WICKLINE, S.
- Venue
- Journal of Thrombosis and Haemostasis
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 9
- Issue
- 7
- Pages
- 1292-1300
- ISSN
- 1538-7836 (ISSN-L)
- PMC
- PMC3686484
- OpenAlex
- W1534143490
- Cited by
- 96
- References
- 36
- Citations by year
- 2025: 4 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 11 · 2019: 4 · 2018: 9 · 2017: 8 · 2016: 8 · 2015: 9 · 2014: 7 · 2013: 7 · 2012: 3
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thrombosis and Haemostasis (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL073646)
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Hematology › Hemostasis and retained surgical items
- Keywords
- thrombin inhibition, perfluorocarbon nanoparticles, PPACK, anticoagulants, acute thrombosis, 19F MRI, 19F magnetic resonance spectroscopy, heparin comparison, activated partial thromboplastin time, nanoparticle retention
- MeSH terms
- Acute Disease, Amino Acid Chloromethyl Ketones, Animals, Binding Sites, Fluorocarbons, Magnetic Resonance Imaging, Partial Thromboplastin Time, Thrombin, Thrombosis, Serine Proteinase Inhibitors, Mice, Nanoparticles
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