Blood clot-targeted nanoparticles

• US 7,220,401 B2
• Filed: 08/20/2002
• Issued: 05/22/2007
• Est. Priority Date: 09/24/1999
• Status: Expired due to Fees

• Current Assignee: Barnes-Jewish Hospital (BJC Health System)
• Original Assignee: Barnes-Jewish Hospital (BJC Health System)
• Inventors: Lanza, Gregory, Wickline, Samuel A.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US10/225,024
• Publication Number:
  US 20030086867A1
• Time in Patent Office: 1,736 Days
• Field of Search: 424/9.52, 424/9.51, 424/9.5, 424/1.21, 424/1.29, 424/9.32, 424/9.323, 424/450, 424/455, 424/489, 514/937
• US Class Current: 424/9.323
• CPC Class Codes: A61K 47/6843 the antibody targeting a material from animals or humans
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• CPC Class Codes: A61K 49/0471 Perflubron, i.e. perfluoroctylbromide, C8F17Br emulsions
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/1812 liposomes, polymersomes, e.g. immunoliposomes
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
• CPC Class Codes: A61K 51/1227 Micelles, e.g. phospholipidic or polymeric micelles
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Emulsions comprising nanoparticles formed from high boiling perfluorochemical substances, said particles coated with a lipid/surfactant coating are made target-specific by directly coupling said nanoparticles to a targeting ligand. The nanoparticles may further include biologically active agents, radionuclides, and/or other imaging agents.

Claims

1. A method to obtain a magnetic resonance image of a blood clot in a subject, which method comprises

administering to said subject an emulsion of nanoparticles, said nanoparticles consisting of liquid perfluorocarbon coated with lipid/surfactant,

wherein said nanoparticles are coupled to at least one targeting ligand that is specific for at least one component characterizing blood clots that binds specifically to fibrin, gpIIb/IIIa, tissue factor/VIIA complex, activated clotting factor Xa, activated clotting factor IXa, or the fibrin condensation product, d-dimer, and

wherein said nanoparticles are also coupled to at least one magnetic resonance imaging (MRI) contrast agent;

allowing the targeting ligand to bind to the blood clot; and

detecting a magnetic resonance image of said blood clot wherein said blood clot is bound to said ligand coupled directly to said lipid/surfactant-coated particles, while said nanoparticles are entirely in the liquid state.

2. The method of claim 1, wherein said MRI contrast agent is a chelated paramagnetic ion.

3. The method of claim 2, wherein the paramagnetic ion is gadolinium ion.

4. The method of claim 1, wherein the perfluorocarbon is selected from the group consisting of perfluorodecalin, perfluorooctane, perfluorodichlorooctane, perfluoro-n-octyl bromide, perfluoroheptane, perfluorodecane, perfluorotripropylamine, perfluortributylamine, and mixtures thereof.

5. The method of claim 4, wherein the perfluorocarbon is perfluoro-n-octyl bromide.

6. The method of claim 1, wherein the targeting ligand is coupled covalently to a component of the lipid/surfactant coating.

7. The method of claim 1, wherein the ligand binds specifically to fibrin.

8. The method of claim 7, wherein said ligand is an antifibrin antibody or an immunoreactive fragment thereof.

9. The method of claim 1, wherein the ligand binds specifically to gpIIb/IIIa.

10. The method of claim 1, wherein the ligand binds specifically to tissue factor/VIIA complex.

11. The method of claim 1, wherein the ligand binds specifically to activated clotting factor Xa.

12. The method of claim 1, wherein the ligand binds specifically to activated clotting factor IXa.

13. The method of claim 1, wherein the ligand binds specifically to fibrin condensation product, d-dimer.