Paramagnetic particles that provide improved relaxivity

• US 20030185760A1
• Filed: 05/21/2002
• Published: 10/02/2003
• Est. Priority Date: 03/26/2002
• Status: Active Grant

• Current Assignee: Barnes-Jewish Hospital (BJC Health System)
• Original Assignee: Barnes-Jewish Hospital (BJC Health System)
• Inventors: Lanza, Gregory, Wickline, Samuel A.
• Granted Patent: US 6,869,591 B2
• Time in Patent Office: Days
• US Class Current: 424/9.321
• CPC Class Codes: A61K 49/1881 wherein the coating consists of chelates, i.e. chelating group complexing a (super)(para)magnetic ion, bound to the surface
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

An improved contrast agent for magnetic resonance imaging comprises particles to each of which is coupled a multiplicity of chelating agents containing paramagnetic ions. In the improved agent, the position of the ion is offset from the surface of the particle so as to improve the relaxivity imparted by the contrast agent.

Claims

1. A contrast agent for magnetic resonance imaging (MRI), which agent comprises particles, wherein said particles are coupled to a chelator containing a paramagnetic ion which ion is positioned offset from the surface of the particles, so as to provide said ion substantial access to hydrogen nuclei in a surrounding liquid, whereby the relaxivity of said nuclei is enhanced.

2. The agent of claim 1, wherein said offset positions said ion at a mean distance of at least 5 Å

from the surface of the particle.

3. The agent of claim 1, wherein said offset is such that the particle provides a ρ

₁ of at least about 0.5×

10⁶ (s*mM)<sup>−

1</sup> or a ρ

₂ of at least about 1×

10⁶ (s*mM)<sup>−

1</sup> at a field strength of 1.5 T on a per particle basis.

4. The agent of claim 1, wherein said offset is such that the particle provides a ρ

₁ of at least about 10 (s*mM)<sup>−

1</sup> or a ρ

₂ of at least about 20 (s*mM)<sup>−

1</sup> at a field strength of 1.5 T on a per ion basis.

5. The agent of claim 1, wherein said offset is such that ρ

₁ is increased at least about 1.5-fold or ρ

₂ is increased at least about 1.5-fold at a field strength of 1.5 T on a per particle basis as compared to ρ

₁ or ρ

₂ of particles wherein the paramagnetic ion resides at less than 5 Å

from the surface.

6. The agent of claim 1, wherein the particles are contained in a liquid emulsion.

7. The agent of claim 6, wherein said particles are nanoparticles comprised of an inert core surrounded by a lipid/surfactant coating.

8. The agent of claim 1, wherein said inert core comprises a perfluorocarbon compound.

9. The agent of claim 1, wherein the particles are liposomes.

10. The agent of claim 1, wherein the particles are solid microspheres or nanospheres.

11. The agent of claim 1, wherein the particles comprise mixtures of fluorocarbons and oils.

12. The agent of claim 1, wherein the chelator is selected from the group consisting of a porphyrin, ethylenediaminetetraacetic acid (EDTA), diethylenetriamine-N,N,N″

,N″

,N″

-pentaacetate (DTPA), 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diacetate, N-2-(azol-1(2)-yl)ethyliminodiacetic acid, 1,4,7,10-tetraazacyclododecane-N,N′

,N″

,N′

″

-tetraacetic acid, 1,7,13-triaza-4,10,16-trioxacyclo-octadecane-N,N′

,N″

-triacetate, tetraethylene glycol,1,5,9-triazacyclododecane-N,N′

,N″

,-tris(methylene)phosphonic acid, and N,N′

,N″

-trimethylammonium chloride.

13. The agent of claim 12, wherein the chelator is DTPA.

14. The agent claim 1, wherein the paramagnetic ion is selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, molybdenum, ruthenium, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, and ytterbium.

15. The agent of claim 14, wherein the paramagnetic ion is gadolinium.

16. The agent of claim 7, wherein the lipid/surfactant coating comprises at least one compound selected from the group consisting of a natural phospholipid, a synthetic phospholipid, a fatty acid, a cholesterol, a lysolipid, a sphingomyelin, a tocopherol, a glucolipid, a stearylamine, a cardiolipin, a lipid with an ether-linker fatty acid, a lipid with an ester linked fatty acid, a polymerized lipid, and a polyethylene glycol-conjugated lipid.

17. The agent of claim 1 wherein said particles are coupled to at least 10,000 chelators per particle.

18. The agent of claim 1, wherein said particles further comprise a coupled target-specific ligand.

19. The agent of claim 18, wherein said target specific ligand is an antibody, an antibody fragment, a peptide, an aptamer, a peptide mimetic, a drug or a hormone.

20. The agent of claim 19, wherein said target specific ligand is an antibody or fragment of an antibody.

21. The agent of claim 20, wherein said antibody is humanized and/or is a single chain F_v antibody.

22. The agent of claim 18, wherein said particles comprise at least about 2 copies of said target-specific ligand per particle.

23. The agent of claim 18, wherein said target-specific ligand is coupled directly to said particles.

24. The agent of claim 1, wherein said particles further comprise a biological agent.

25. A method for magnetic resonance imaging (MRI), which method comprises administering the agent of claim 1 to a subject, permitting said agent to accumulate at a site of said subject for which an image is desired;

and

detecting an image of said site generated by hydrogen nuclei at said site.

26. The method of claim 25, wherein said site comprises a specific binding partner for a ligand, and wherein said particles further are coupled to a ligand specific for said specific binding partner.

27. A method for magnetic resonance imaging (MRI), which method comprises administering the agent of claim 8 to a subject, permitting said agent to accumulate at a site of said subject for which an image is desired;

and

detecting an image of said site generated by hydrogen nuclei at said site.

28. The method of claim 27, wherein said site comprises a specific binding partner for a ligand, and wherein said particles further are coupled to a ligand specific for said specific binding partner.

29. The method of claim 28, which further comprises detecting an image generated by ¹⁹F contained in said particles at said site.

30. The method of claim 29, which further comprises detecting an image generated by ¹⁹F contained in said particles at said site.