Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2001-04-11
2003-03-18
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009323, C424S009360
Reexamination Certificate
active
06534039
ABSTRACT:
BACKGROUND OF THE INVENTION
Magnetic materials have many utilities including use in computer disk memory storage, audio and video recording tape, sensors, coatings, magneto-optical devices, as magnetic resonance imaging (MRI) contrast enhancement agents, and biolabels for molecular or cell tagging or separations. Typically iron oxides, hematite, Fe
2
O
3
, maghemite, gamma-Fe
2
O
3
and magnetite, Fe
3
O
4
are used, or various alloys, such as in alnico magnets (aluminum, nickel, cobalt), or mixed oxide materials with octahedral Fe
3+
ions such as, the spinels BaFe
12
O
19
and Ba
2
Mn
2
Fe
12
O
22
, used in magnetic tapes. Gadolinium, complexed with DTPA (diethylenetriamine pentaacetic acid), Gd-DTPA, is commonly used for MRI enhancement.
Unfortunately, currently available magnetic materials have a number of shortcomings which limit the potential of the applications in which they are used. For example, magnetic recording media is far below its potential density due to a lack of precise control in preparing and magnetically isolating storage bits, and organizing regular smaller elements into arrays. This is largely because the recording media is generated by annealing bulk coatings which form irregular domains. In order to provide adequate information isolation, larger than desired areas must be assigned to each information bit. If the magnetic recording media was instead constructed from optimally sized magnetic nanoparticles, higher recording densities could be utilized without detracting from overall quality. In the medical field, iron oxide nanoparticles used as imaging agents are irregular in size, have associated toxicity, and have irregular biodistributions when administered in vivo. The accepted MRI contrast enhancement agent, Gd-DTPA, has a short half-life in the bloodstream, which precludes uses which require longer visualization periods. Also, when Gd-DTPA is conjugated to a targeting moiety, such as an antibody, imaging signal generated at the target is too weak to be generally useful for targeted imaging of, for example, tumors, clots, or atherosclerotic plaques. The therapeutic application of oscillating magnetic fields to magnetic particles, such as iron distributed at a site in the body, has been proposed for use in heating tumors to destroy them. Success however, has been limited by poor specific tumor uptake of particles, lack of sufficient particle accumulation, and commensurate particle toxicity.
The synthesis of magnetic nanoparticles generally involves grinding of macroscopic magnets, sonication, the formation of micelles, pH adjustment, or controlled oxidation. Unfortunately, these presently used methods produce heterogeneously sized particles which are suboptimal or precludes their use in many applications. There is a need in the related arts for uniform, small magnetic materials, especially less than 10 nm.
The magnetic nanoparticles currently available in the art usually aggregate during formation and use, as evidenced from electron micrographs of the material. Aggregation is an undesirable property. An additional undesirable property is a lack of stability of the magnetic materials. Magnetic particles in the art exhibit altered and degraded magnetic properties after short periods of storage. Many iron particles continue to oxidize, as is common with rusting.
It is often necessary to further modify the magnetic particles prior to use. For instance, many magnetic materials must be coated. Coating is by mixing the particle with sugars, polymers and various other substances. These coatings suffer from the instability of adsorption. Another modification is the covalent attachment of molecules to the particles. One example is the attachment of a molecule to the oxygen atom of an iron oxide particle. Although the produce has a covalent linkage, which is useful for many applications, there are many other drawbacks associated with utilizing iron particles as magnetic material, such as instability, poor size distributions, toxicity and aggregation, which limits use.
SUMMARY OF THE INVENTION
One aspect of the present invention is a method for in vivo imaging an internal component of an individual, such as tissue, utilizing an extended cobalt complex as a contrast enhancement agent. The extended cobalt complex is comprised of cobalt atoms, a carboxylate ligand, an amine ligand, and a multidentate thiol-containing organic ligand, the cobalt atoms being linked to thiol groups and counter ions. The cobalt extended complex is characterized as stable, water soluble, non-aggregating, magnetic, and from 0.5 to 10 nm in size. The method comprises administering the extended cobalt complex to the individual to contact the tissue with the extended cobalt complex, and performing magnetic resonance imaging on the individual to image the tissue. In one embodiment, the tissue which is imaged is a tumor. This method is highly useful for clinical diagnosis of a tumor. In another embodiment, the tissue is regenerating from a wound. The extended cobalt complex is optionally linked to a biomolecule, preferably a binding moiety which specifically targets the extended cobalt complex to a target molecule selectively expressed on the tissue which is to be imaged.
Another aspect of the present invention relates to a method for visually detecting the presence of an antigen in a sample using an antibody which specifically binds the antigen, the antibody being coupled to an extended cobalt complex which has a characteristic color. In the method, the antibody is contacted to the sample under conditions appropriate for antibody-antigen binding, the sample is washed to remove unbound antibody, and the presence of the remaining extended cobalt complex is visually detected by its characteristic color.
DETAILED DESCRIPTION OF THE INVENTION
Aspects of the present invention relate to the development of a new class of organic magnetic material in the form of nanoparticles, which contains nickel and/or cobalt. Magnetic nanoparticles of the prior art are solid particles of magnetic material, such as cobalt or iron oxide. Such particles are either used as is, or coated, for example, with dextrans. At the other end of the size spectrum are single magnetic ions complexed with various organic molecules, such as gadolinium-DTPA. In the present invention, a magnetic nanoparticle composition is synthesized from a small peptide containing a thiol group (referred to herein as a thiol-containing peptide, or a thiol peptide) and various counter ions (referred to also as ligands) to form an extended complex in which multiple cobalt or nickel atoms are linked with multiple peptides such that the apparent molecular weight is greater than about 3,000 daltons (as gauged by exclusion on a gel filtration column with water as the eluent). The extended complex does not pass through a 3,000 molecular weight (nominal) filter (Amicon Centricon 3), but mostly passes through a 10,000 molecular weight filter (Amicon Centricon 10). The complex formed is termed “extended” or “large” because it is much larger in size than low molecular weight complexes, such as Gd-DTPA (molecular weight of 548).
Another aspect of the present invention relates to the method of synthesis of the extended complex. Unlike existing methods for synthesis of magnetic materials, which use sonication, micelles, strong reducing agents, grinding, oxidation, or simple complexion, cobalt or nickel metal salts are complexed with a thiol peptide (glutathione), citrate, ammonia, and chloride in basic solution to form the extended complex. This method was discovered fortuitously while searching for a novel form of magnetic nanoparticle. The method described herein is a refinement of the original procedure During synthesis, an instant color change of the solution from light red or pink to dense, almost opaque brown, without precipitation, occurs when synthesizing extended cobalt complexes. Color change from green to dense, almost opaque brown, without precipitation, occurs when synthesizing extended nickel complexes. The observed color changes were initiall
Atwood Pierce
Farrell Kevin M.
Hartley Michael G.
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