Nanoparticle contrast agents for diagnostic imaging

1. A method for making a plurality of nanoparticles having a core-shell structure, the method comprising:

a) providing a core precursor material comprising a transition metal alkoxide for generating a core having a core surface essentially free of silica;

b) providing a shell precursor material comprising a tri-alkoxy silane-functionalized zwitterionic compound; and

c) reacting the core precursor material with the shell precursor material in presence of an acid to generate the plurality of nanoparticles having a core-shell structure,

wherein the tri-alkoxy silane-functionalized zwitterionic compound binds to the core of the nanoparticle at the core surface without any intervening silica layer.

2. The method of claim 1 , further comprising providing a zwitterionic compound and a silane compound, and reacting the zwitterionic compound with the silane compound to produce the tri-alkoxy silane-functionalized zwitterionic compound used in part (b) of claim 1 .

3. The method of claim 2 , further comprising hydrolysing the zwitterionic compound before reacting it with the silane compound to form the tri-alkoxy silane functionalized zwitterionic moiety used in part (b) of claim 1 .

4. The method of claim 1 , wherein the tri-alkoxy silane-functionalized zwitterionic compound 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.

5. The method of claim 4 , 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.

6. The method of claim 4 , 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.

7. The method of claim 4 , 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.

8. The method of claim 4 , wherein a silicon atom of the tri-alkoxy silane-functionalized zwitterionic compound is connected to the positively or negatively charged moiety via a second spacer group.

9. The method of claim 8 , 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.

10. The method of claim 1 , wherein the tri-alkoxy silane-functionalized zwitterionic compound 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.

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

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

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

14. The method of claim 13 , wherein the superparamagnetic material comprises iron, manganese, copper, cobalt, nickel, or combinations thereof.

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

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

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

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

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

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

21. The method of claim 20 , wherein the purifying comprises use of dialysis, tangential flow, filtration, or diafiltration.

22. The method of claim 20 , further comprising isolating the purified nanoparticles.