Treating water insoluble nanoparticles with hydrophilic alpha-hydroxyphosphonic acid conjugates, the so modified nanoparticles and their use as contrast agents

Patent metadata

Field	Value
Publication number	US-2016038617-A1
Application number	US-201514919077-A
Country	US
Kind code	A1
Filing date	Oct 21, 2015
Priority date	Oct 30, 2009
Publication date	Feb 11, 2016
Grant date	—

Abstract

The present application discloses treating water insoluble nanoparticles, particularly nanoparticles of metals and metal compounds which find utility in diagnostic imaging such as MR and X-ray imaging, with an alpha-hydroxyphosphonic acid conjugate with a hydrophilic moiety to render the nanoparticles sufficiently hydrophilic to find utility in diagnostic imaging. Among the modified hydrophilic nanoparticles disclosed are those in which the hydrophilic moieties of the modifying conjugate are ethylene oxide based polymers and copolymers and zwitterions and the nanoparticles are composed of transition metal oxides such as superparamagnetic iron oxide and tantalum oxide. Disclosed are nanoparticles which are sufficiently hydrophilic to form stable aqueous colloidal suspensions. Also disclosed is diagnostic imaging such as MR and X-ray using the modified hydrophilic nanoparticles as contrast agents.

First claim

1 . A diagnostic agent composition suitable for injection into a mammalian subject, comprising:
iron oxide nanoparticles to which are adhered alpha-hydroxy phosphonate moieties; wherein said alpha-hydroxy phosphonate moieties has the formula:

wherein S is a spacer, L is a linkage between S and R, R is a poly(ethylene oxide) moiety, and wherein m and p are independently 1-5, n and o are independently 0-5; and
a pharmaceutically acceptable carrier or excipient.

2 . The diagnostic agent composition of claim 1 , wherein S is a direct bond, an unsubstituted or a substituted aliphatic or cycloaliphatic group, an unsubstituted or a substituted aryl group, a heteroaliphatic group, a heteroaryl group, or combinations thereof.

3 . The diagnostic agent composition of claim 1 , wherein S is a straight chain alkyl group of 1 to 10 carbon atoms in length and n is equal to 1.

4 . The diagnostic agent composition of claim 1 , wherein L is a direct bond, a carbonyl group, an ether group, an amide group, an ester group, a carbamate group, an urea group, or combinations thereof.

5 . The diagnostic agent composition of claim 1 , wherein L is a direct bond.

6 . The diagnostic agent composition of claim 1 , wherein p is equal to 1.

7 . The diagnostic agent composition of claim 1 , wherein the poly(ethylene oxide) moiety comprise a methoxy terminal group.

8 . The diagnostic agent composition of claim 7 , wherein the poly(ethylene oxide) moiety has a molecular weight less than or equal to about 5000 daltons.

9 . The diagnostic agent composition of claim 7 , wherein the poly(ethylene oxide) moiety has a molecular weight less than or equal to about 2000 daltons.

10 . The diagnostic agent composition of claim 7 , wherein the poly(ethylene oxide) moiety has a molecular weight less than or equal to about 350 daltons.

11 . The diagnostic agent composition of claim 1 , wherein the nanoparticles have an average hydrodynamic particle size (D H ) in 150 mM NaCl water as determined by dynamic light scattering of up to about 500 nm.

12 . The diagnostic agent composition of claim 1 , wherein the nanoparticles have an average hydrodynamic particle size (D H ) in 150 mM NaCl water as determined by dynamic light scattering of up to about 8 nm.

13 . The diagnostic agent composition of claim 1 , wherein the nanoparticles have a zeta potential between about −15 mV and +15 mV.

14 . The diagnostic agent composition of claim 1 , wherein the carrier is an isotonic aqueous medium.

15 . The diagnostic agent composition of claim 1 , which is suitable for injection into a human subject.

16 . The diagnostic agent composition of claim 1 , in which said nanoparticles are sufficiently hydrophilic to form a stable aqueous colloidal suspension that exhibits no substantial change in hydrodynamic diameter (D H ) as determined by dynamic light scattering in 150 mM NaCl water after tangential flow filtration and storage for one week at room temperature.

17 . A diagnostic agent composition comprising:
a superparamagnetic iron oxide nanoparticle having at least one alpha-hydroxy phosphonate moiety adhered to the superparamagnetic iron oxide nanoparticle, wherein the at least one alpha-hydroxy phosphonate moiety has the formula:

wherein S is a spacer and R is a poly(ethylene oxide) moiety.

18 . The diagnostic agent composition of claim 17 , wherein S is a —CH 2 -group and the poly(ethylene oxide) moiety comprises a methoxy terminal group.

19 . The diagnostic agent composition of claim 18 , wherein the poly(ethylene oxide) moiety has a molecular weight less than or equal to about 5000 daltons.

20 . A process of utilizing iron oxide nanoparticles to which are adhered alpha-hydroxy phosphonate moieties, in diagnostic imaging comprising
a. administering said iron oxide nanoparticles to a subject; and b. subjecting said subject to diagnostic imaging in which said nanoparticles act as a contrast agent; wherein said alpha-hydroxy phosphonate moieties has the formula:

wherein S is a spacer, L is a linkage between S and R, R is a poly(ethylene oxide) moiety and, wherein m and p are independently 1-5, and n and o are independently 0-5.

21 . The process of claim 20 , wherein said nanoparticles are administered by injection, inhalation or ingestion.

22 . The process of claim 20 , wherein the imaging is by magnetic resonance (MR).

Assignees

• Gen Electric

Inventors

• Bales Brian Christopher
• Hay Bruce Allan
• Kandapallil Binil Itty Ipe

Classifications

• A61K49/1842

  the small organic molecule being a phosphate or a phosphonate, not being a phospholipid · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• A61K49/186

  the organic macromolecular compound being polyethyleneglycol [PEG] · CPC title

• A61K49/0428 Primary

  Surface-modified nanoparticles, e.g. immuno-nanoparticles · CPC title

• A61K49/1857 Primary

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