Thrombin‐inhibiting perfluorocarbon nanoparticles provide a novel strategy for the treatment and magnetic resonance imaging of acute thrombosis
| Autor: | Li He, Gregory M. Lanza, Samuel A. Wickline, Jacob W. Myerson, Douglas M. Tollefsen |
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| Rok vydání: | 2011 |
| Předmět: |
Serine Proteinase Inhibitors
medicine.drug_class Pharmacology Article Amino Acid Chloromethyl Ketones Mice Thrombin In vivo Antithrombotic medicine Animals Fluorocarbons Binding Sites medicine.diagnostic_test Chemistry Anticoagulant Thrombosis Hematology Heparin medicine.disease Magnetic Resonance Imaging In vitro Biochemistry Acute Disease Nanoparticles Partial Thromboplastin Time circulatory and respiratory physiology medicine.drug Partial thromboplastin time |
| Zdroj: | Journal of Thrombosis and Haemostasis. 9:1292-1300 |
| ISSN: | 1538-7836 |
| DOI: | 10.1111/j.1538-7836.2011.04339.x |
| Popis: | Summary. 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 19F 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. 19F 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. |
| Databáze: | OpenAIRE |
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