NANOPARTICLE CONTRAST AGENTS FOR DIAGNOSTIC IMAGING

• US 20100166665A1
• Filed: 12/29/2008
• Published: 07/01/2010
• Est. Priority Date: 12/29/2008
• Status: Active Grant

• Current Assignee: GE Healthcare Limited (General Electric Company)
• Original Assignee: General Electric Company
• Inventors: Colborn, Robert Edgar, Hay, Bruce Allan, Bales, Brian Christopher, Butts, Matthew David, Torres, Andrew Soliz, Marino, Michael Ernest, Bonitatibus, Peter John JR., Kulkarni, Amit Mohan
• Granted Patent: US 8,728,529 B2
• Time in Patent Office: Days
• US Class Current: 424/9.320
• CPC Class Codes: A61K 49/0428 Surface-modified nanoparticles, e.g. immuno-nanoparticles
• CPC Class Codes: A61K 49/1848 the small organic molecule being a silane
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Compositions of nanoparticles functionalized with at least one zwitterionic moiety, methods for making a plurality of nanoparticles, and methods of their use as diagnostic agents are provided. The nanoparticles have characteristics that result in minimal retention of the particles in the body compared to other nanoparticles. The nanoparticle comprises a core, having a core surface essentially free of silica, and a shell attached to the core surface. The shell comprises at least one silane-functionalized zwitterionic moiety.

Claims

1. A method for making a plurality of nanoparticles, the method comprising:

a) providing a core having a core surface essentially free of silica; and

b) disposing a shell attached to the core surface, wherein the shell comprises a silane-functionalized zwitterionic moiety.

2. The method of claim 1, wherein the providing a core comprises providing a first precursor material, wherein the first precursor material comprises at least one transition metal.

3. The method of claim 2, further comprising reacting the first precursor material to generate the core, wherein the core comprises at least one transition metal.

4. The method of claim 1, wherein the disposing a shell attached to the core surface comprises providing a second precursor material and reacting the second precursor material with the core to produce a shell disposed on the core.

5. The method of claim 4, wherein the second precursor material comprises a silane moiety.

6. The method of claim 5, further comprising hydrolysing the silane moiety before reacting with the core.

7. The method of claim 5, further comprising providing a zwitterionic moiety and reacting the zwitterionic moiety with the silane moiety to produce a silane-functionalized zwitterionic moiety.

8. The method of claim 7, further comprising hydrolysing the zwitterionic moiety before reacting with the silane moiety.

9. The method of claim 4, wherein the second precursor material comprises a silane-functionalized zwitterionic moiety.

10. The method of claim 9, further comprising hydrolysing the silane-functionalized zwitterionic moiety before reacting with the core.

11. The method of claim 1, wherein the silane-functionalized zwitterionic moiety comprises a positively charged moiety, a negatively charged moiety and a first spacer group in between the positively charged moiety and the negatively charged moiety.

12. The method of claim 11, wherein the positively charged moiety comprises protonated primary amines, protonated secondary amines, protonated tertiary alkyl amines, protonated amidines, protonated guanidines, protonated pyridines, protonated pyrimidines, protonated pyrazines, protonated purines, protonated imidazoles, protonated pyrroles, quaternary alkyl amines, or combinations thereof.

13. The method of claim 11, wherein the negatively charged moiety comprises deprotonated carboxylic acids, deprotonated sulfonic acids, deprotonated sulfinic acids, deprotonated phosphonic acids, deprotonated phosphoric acids, deprotonated phosphinic acids, or combinations thereof.

14. The method of claim 11, wherein the first spacer group comprises alkyl groups, aryl groups, substituted alkyl and aryl groups, heteroalkyl groups, heteroaryl groups, carboxy groups, ethers, amides, esters, carbamates, ureas, straight chain alkyl groups of 1 to 10 carbon atoms in length, or combinations thereof.

15. The method of claim 11, wherein a silicon atom of the silane-functionalized zwitterionic moiety is connected to the positively or negatively charged moiety via a second spacer group.

16. The method of claim 15, wherein the second spacer group comprises alkyl groups, aryl groups, substituted alkyl and aryl groups, heteroalkyl groups, heteroaryl groups, carboxy groups, ethers, amides, esters, carbamates, ureas, straight chain alkyl groups of 1 to 10 carbon atoms in length, or combinations thereof.

17. The method of claim 1, wherein the silane-functionalized zwitterionic moiety is derived from a hydrolysis product of a precursor tri-alkoxy silane.

18. The method of claim 17, wherein the precursor tri-alkoxy silane comprises N,N-dimethyl-3-sulfo-N-(3-(trimethoxysilyl)propyl)propan-1-aminium, 3-(methyl(3-(trimethoxysilyl)propyl)amino)propane-1-sulfonic acid, 3-(3-(trimethoxysilyl)propylamino)propane-1-sulfonic acid, 2-(2-(trimethylsilyl)ethoxy(hydroxy)phosphoryloxy)-N,N,N-trimethylethanaminium, 2-(2-(trimethoxysilyl)ethyl(hydroxy)phosphoryloxy)-N,N,N-trimethylethanaminium, N,N,N-trimethyl-3-(N-3-(trimethoxysilyl)propionylsulfamoyl)propan-1-aminium, N-((2H-tetrazol-5-yl)methyl)-N,N-dimethyl-3-(trimethoxysilyl)propan-1-aminium, N-(2-carboxyethyl)-N,N-dimethyl-3-(trimethoxysilyl)propan-1-aminium, 3-(methyl(3-(trimethoxysilyl)propyl)amino)propanoic acid, 3-(3-(trimethoxysilyl)propylamino) propanoic acid, N-(carboxymethyl)-N,N-dimethyl-3-(trimethoxysilyl) propan-1-aminium, 2-(methyl(3-(trimethoxysilyl)propyl)amino)acetic acid, 2-(3-(trimethoxysilyl)propylamino)acetic acid, 2-(4-(3-(trimethoxysilyl)propylcarbamoyl)piperazin-1-yl)acetic acid, 3-(4-(3-(trimethoxysilyl)propylcarbamoyl)piperazin-1-yl)propanoic acid, 2-(methyl(2-(3-(trimethoxysilyl)propylureido)ethyl)amino)acetic acid, 2-(2-(3-(trimethoxysilyl)propylureido)ethyl)aminoacetic acid, or combinations thereof.

19. The method of claim 1, wherein the core comprises tungsten, tantalum, hafnium, zirconium, molybdenum, silver, zinc, or combinations thereof.

20. The method of claim 1, wherein the core comprises tantalum oxide.

21. The method of claim 1, wherein the core comprises superparamagnetic material.

22. The method of claim 21, wherein the superparamagnetic material comprises iron, manganese, copper, cobalt, nickel, or combinations thereof.

23. The method of claim 1, wherein the core comprises a superparamagnetic iron oxide.

24. The method of claim 1, wherein the plurality of nanoparticles has a median particle size up to about 50 nm.

25. The method of claim 1, wherein the plurality of nanoparticles has a median particle size up to about 10 nm.

26. The method of claim 1, wherein the plurality of nanoparticles has a median particle size up to about 6 nm.

27. The method of claim 1, further comprising fractionating the plurality of nanoparticles, wherein the fractionating comprises filtering the nanoparticles.

28. The method of claim 1, further comprising purifying the plurality of nanoparticles to form a plurality of purified nanoparticles.

29. The method of claim 28, wherein the purifying comprises use of dialysis, tangential flow, filtration, or diafiltration.

30. The method of claim 28, further comprising isolating the purified nanoparticles.