Antithrombotic nanoparticle
The present invention encompasses an antithrombotic nanoparticle and use thereof.
1. A method of inhibiting thrombin activation of a protein-activated receptor (PAR) in a subject, the method comprising administering to the subject an antithrombotic nanoparticle comprising a core and an outer layer,
wherein the core of the antithrombotic nanoparticle comprises a perfluorocarbon that is a liquid at about 37° C. and the outer layer comprises a mixture of a lipid and a surfactant;
wherein the exterior of the antithrombotic nanoparticle comprises a direct thrombin inhibitor covalently conjugated to the exterior via the lipid component of the nanoparticle's outer layer, such that the antithrombotic nanoparticle has a second order kinetic constant for the direct thrombin inhibitor-thrombin interaction that is greater than the same kinetic constant of the direct thrombin inhibitor by itself; and
wherein the antithrombotic nanoparticle is antithrombotic but does not substantially alter the clotting time of a subject's blood plasma.
2. The method of claim 1 , wherein the nanoparticle further comprises an anti-platelet agent.
3. The method of claim 1 , wherein the direct thrombin inhibitor is bivalirudin.
4. The method of claim 1 , wherein the direct thrombin inhibitor is D-phenylalyl-L-prolyl-L-arginyl-chloromethyl ketone (PPACK).
5. The method of claim 1 , wherein the PAR is PAR-1, PAR-3, or PAR-4.
6. The method of claim 1 , wherein the PAR is PAR-1.
7. A method of inhibiting thrombin activation of a protein-activated receptor (PAR) in an organ, the method comprising contacting the organ with an antithrombotic nanoparticle comprising a core and an outer layer,
wherein the core of the antithrombotic nanoparticle comprises a perfluorocarbon that is a liquid at about 37° C. and the outer layer comprises a mixture of a lipid and a surfactant;
wherein the exterior of the antithrombotic nanoparticle comprises a direct thrombin inhibitor covalently conjugated to the exterior via the lipid component of the nanoparticle's outer layer, such that the antithrombotic nanoparticle has a second order kinetic constant for the direct thrombin inhibitor-thrombin interaction that is greater than the same kinetic constant of the direct thrombin inhibitor by itself; and
wherein the antithrombotic nanoparticle is antithrombotic but does not substantially alter the clotting time of a subject's blood plasma.
8. The method of claim 7 , wherein the nanoparticle further comprises an anti-platelet agent.
9. The method of claim 7 , wherein the direct thrombin inhibitor is bivalirudin.
10. The method of claim 7 , wherein the direct thrombin inhibitor is D-phenylalyl-L-prolyl-L-arginyl-chloromethyl ketone (PPACK).
11. The method of claim 7 , wherein the PAR is PAR-1, PAR-3, or PAR-4.
12. The method of claim 7 , wherein the PAR is PAR-1.