Shape-controlled magnetic nanoparticles as T1 contrast agents for magnetic resonance imaging

Patent metadata

Field	Value
Publication number	US-9867889-B2
Application number	US-201113821100-A
Country	US
Kind code	B2
Filing date	Sep 26, 2011
Priority date	Sep 29, 2010
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

Methods are provided for the generation of nanostructures suitable for use in magnetic resonance imaging where the nanostructures have at least one dimension of about 2 nm or less. In particular, the methods comprise the selective use of incubation temperatures that result in the controlled removal of ligands from metallic cores to which they are attached, allowing the metallic cores or the precursor moieties to unite to form nanostructures of defined and predictable shapes, but having at least one dimension significantly less that at least one other dimension. Accordingly, the nanostructures of the disclosure may be ultrathin sheets, rods, whiskers and the like, or even structures that are thin and porous resembling rice grains. The temperatures useful in the methods of the disclosure are less than 300° C. and allow for progressive elevation of the incubation temperature. The methods are especially advantageous for synthesizing nanoparticles that may be administered to an animal or human subject for imaging with magnetic resonance. Accordingly, the nanostructures of the disclosure comprise a metallic core, most typically, but not necessarily limited to, a ferrite moiety that can be a ferrous or ferric ion alone or in combination with other metallic elements. However, the methods of the disclosure are also suitable for generating nanostructures with non-ferrous cores such as magnesium or manganese cores.

First claim

I claim:

1. A method of synthesizing ultrathin nanostructures, wherein the method comprises the steps of:
(a) obtaining a metallic core-ligand complex precursor comprising a metallic moiety and a plurality of ligands attached to said metallic moiety, wherein the plurality of ligands comprises one or more ligands that are more weakly bound and one or more ligands that are more strongly-bound than the more weakly bound ligands, wherein the more weakly bound ligands are characterized in that at an incubation temperature the more weakly bound ligands dissociate and the more strongly bound ligands remain attached; and
(b) incubating the metallic core-ligand complex precursor mix at the incubation temperature, wherein the incubation temperature is selected from the group of: from about 100° C. to about 300° C., from about 100° C. to about 200° C., from about 100° C. to about 175° C., from about 100° C. to about 150° C., about 300° C., about 250° C., about 230° C., about 225° C., about 200° C., about 180° C., about 175° C., about 170° C., about 150° C., and about 125° C.,
wherein the incubation temperature is selected to generate a population of ultrathin nanostructures by a process of thermal displacement of some or all of the more weakly-bound ligand(s) from the metallic core,
wherein the ultrathin nanostructures are a nanowhisker, a nanotube, or a nanorice having a diameter of about 4 nm or less and a longest dimension about 10 nm to 500 nm.

2. The method of claim 1 , wherein the step of obtaining a metallic core-ligand complex precursor comprises mixing a metallic core, at least one ligand species, and an organic solvent, thereby forming a metallic core-ligand complex precursor:organic solvent mix.

3. The method of claim 1 , wherein the diameter is about 1 nm to about 4 nm.

4. The method of claim 1 , wherein the diameter is about 2 nm.

5. The method of claim 1 , wherein the metallic core is selected from the group consisting of: a magnetic ferrite-based moiety selected from ferric oxide, ferrous oxide, a ferric ion, a ferrous ion, a manganese ferrite, a zinc ferrite, a copper ferrite, a chrome ferrite, a cobalt ferrite, a nickel ferrite, a non-ferrous metallic ion, and any combination thereof.

6. The method of claim 1 , wherein the plurality of ligands attached to the metallic core-ligand complex comprises at least one fatty acid species, at least one non-fatty acid species, or at least one fatty acid species combined with at least one non-fatty acid species.

7. The method of claim 6 , wherein the at least one fatty acid species is selected from the group consisting of: a long-chain saturated fatty acid, a long-chain mono-unsaturated fatty acid, and a long-chain unsaturated fatty acid.

8. The method of claim 6 , wherein the at least one fatty acid species is selected from the group consisting of: myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, eicosenoic acid, mead acid, and nervonic acid.

9. The method of claim 6 , wherein the at least one fatty acid is oleic acid.

10. The method of claim 6 , wherein the at least one non-fatty acid ligand is selected from the group consisting of: oleic acid, tri-N-octylphosphine oxide (TOPO), oleylamine, a Good's buffer, biotin, dopamine, histamine, a liquid crystal molecule, or any combination thereof.

11. The method of claim 1 , wherein the step of obtaining a metallic core-ligand complex precursor comprises incubating a ferrite, a ferric salt, a ferrous salt, or a non-ferrous salt, with oleic acid or a salt thereof.

12. The method of claim 1 , wherein the incubation temperature is selected to form a nanowhisker.

13. The method of claim 2 , wherein the metallic core-ligand complex comprises a ferric oxide complexed with a plurality of oleic acid moieties, and wherein said complex is incubated in the organic solvent at about 150° C., thereby forming a population of nanowhiskers.

14. A nanostructure synthesized by a method according to claim 1 .

15. A pharmaceutically acceptable composition comprising a nanostructure synthesized by a method according to claim 1 and a pharmaceutically acceptable carrier.

16. The pharmaceutically acceptable composition of claim 15 , wherein the pharmaceutically acceptable composition is formulated to provide a high-contrast magnetic resonance image of a recipient animal or human subject.

17. An ultrathin nanostructure comprising a metallic core, wherein the ultrathin nanostructure is a nanowhisker, a nanotube, or a nanorice having a diameter of about 1 nm to about 4 nm and a longest dimension about 10 nm to 500 nm, and
wherein the nanostructure has a substantially reduced relaxivity compared to a nanostructure having dimensions of at least 4 nm.

18. The ultrathin nanostructure of claim 17 , wherein the diameter is about 2 nm or less.

19. The ultrathin nanostructure of claim 17 , wherein the metallic core is a magnetic ferrite-based moiety selected from the group consisting of: a ferric oxide, a ferrous oxide, a ferric ion, a ferrous ion, a manganese ferrite, a zinc ferrite, a copper ferrite, a chrome ferrite, a cobalt ferrite, and a nickel ferrite.

20. The ultrathin nanostructure of claim 17 , wherein the ultrathin nanostructure is a nanowhisker.

21. The ultrathin nanostructure of claim 17 , further comprising a biocompatible coating.

22. The ultrathin nanostructure of claim 17 , further comprising a targeting ligand disposed on the surface of the ultrathin nanoparticle.

23. The ultrathin nanostructure of claim 17 , further comprising at least one of the group consisting of: polyacrylic acid (PAA), polyethyleneimine (PEI), glutathione (GSH), lactobionic acid (LBA), histamine, dopamine, L-DOPA, and biotin disposed on the ultrathin nanostructure.

24. The method of claim 1 , wherein the longest dimension is about 10 nm to 30 nm.

25. The ultrathin nanostructure of claim 17 , wherein the longest dimension is about 10 nm to 30 nm.

Assignees

• Bao Yuping Y
• Univ Alabama

Inventors

• Bao Yuping Y

Classifications

• Y10T428/2982

  Particulate matter [e.g., sphere, flake, etc.] · CPC title

• A61K49/1854

  the organic macromolecular compound being obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly(meth)acrylate, polyacrylamide, polyvinylpyrrolidone, polyvinylalcohol · CPC title

• A61K49/1833

  having a (super)(para)magnetic core coated or functionalised with a small organic molecule (oligomeric, polymeric, dendrimeric A61K49/1851) · CPC title

• A61K49/1839 Primary

  the small organic molecule being a lipid, a fatty acid having 8 or more carbon atoms in the main chain, or a phospholipid · CPC title

• A61K49/1857

  the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA · CPC title