Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
2000-07-21
2003-02-18
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C556S148000, C530S304000, C530S391700, C424S001490, C424S001690, C424S001730, C424S178100, C424S179100
Reexamination Certificate
active
06521773
ABSTRACT:
BACKGROUND—FIELD OF INVENTION
This invention relates to production and use of cobalt and nickel magnetic complexes having an organic component.
BACKGROUND—DISCUSSION OF PRIOR ART
Magnetic Materials
Magnetic materials have many applications including use in computer disk memory storage, audio and video recording tape, sensors, coatings, magneto-optical devices, as magnetic resonance imaging (MRI) contrast 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 the currently available materials have limitations and a number of shortcomings for various applications. Magnetic recording media is far below its potential density due to lack of precise control in preparing and magnetically isolating storage bits and organizing regular smaller elements in arrays. Bulk coatings are annealed and form irregular domains. To provide adequate isolation, larger than desired areas must be assigned to each information bit. Construction instead from optimally sized magnetic nanoparticles could greatly improve recording densities. In the medical field, iron oxide nanoparticles have been used as imaging agents, but these are irregular in size, have associated toxicity, and have imperfect biodistributions when administered in vivo. Gd-DTPA is an accepted MRI contrast agent but has a short blood half life limiting uses requiring longer visualization periods; also when conjugated to a targeting moiety, such as an antibody, it does not generate enough signal to be generally useful for targeted imaging of, for example, tumors, clots, or atherosclerotic plaques. Iron magnetic particles heat up in oscillating magnetic fields, and this effect has been proposed for use in heating tumors to destroy them. Success has been limited by poor specific tumor uptake, lack of sufficient total accumulation, and commensurate toxicity.
Synthesis of magnetic nanoparticles has been by various methods including grinding of macroscopic magnets, use of sonication, micelles, pH adjustment, and controlled oxidation. Unfortunately these lead to heterogeneously sized particles making them undesirable for many applications. It has been difficult to produce uniform small magnetic materials, especially less than 10 nm. These small sizes would be desirable for in vivo use and for improved magnetic storage media.
Another significant problem with formation of magnetic nanoparticles is that they usually aggregate. Most of the reports of the synthesis of magnetic nanoparticles that show electron micrographs of the material clearly demonstrate this problem.
A further problem with many magnetic materials is stability. The particles show altered and degraded magnetic properties after short periods of storage. Many iron particles continue to oxidize, as is common with rusting.
Coating of magnetic particles is important to many applications and has been achieved by mixing the particle with sugars, polymers and various other substances. These suffer from the instability of adsorption since there is some desorption rate. Other particles have been covalently attached to, such as linking to the oxygen of iron oxide particles. Although covalent, the many drawbacks of iron particles, such as instability, poor size distributions, toxicity and aggregation, limit their use.
SUMMARY
The present invention describes a method to synthesize a new class of magnetic materials composed of nickel and cobalt or cobalt
ickel extended complexes. Also disclosed is the covalent linking of these nanoparticles to antibodies or other molecules for targeted delivery, alteration of surface properties, or for incorporation with other materials.
DETAILED DESCRIPTION
Object
It is the object of the present invention to provide a new class of organic magnetic complexes containing nickel and/or cobalt with novel properties, which can also be covalently attached to other molecules.
Unusual Properties
A new class of magnetic material is herein described. Previously, most magnetic nanoparticles reported were solid particles of some magnetic material, such as cobalt or iron oxide; such particles were 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 instant invention, in one embodiment, a small peptide containing a thiol group (“thiol-containing peptide”, or “thiol peptide”) and various counter ions ligands are used to form extended complexes that link multiple cobalt or nickel atoms 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 complexes also do not pass through a 3,000 molecular weight (nominal) filter (Amicon Centricon 3), but mostly pass through a 10,000 molecular weight filter (Amicon Centricon 10). Such complexes are termed “extended” or “large” since they differ from low molecular weight complexes such as Gd-DTPA (molecular weight of 548), in that they are much larger in size. The extended complexes are highly water soluble and can be dried, then resuspended easily in water, with no apparent alteration. By electron microscopy, the resultant complexes do not typically have the cobalt or nickel as a dense solid core of metal, but appear to form structures about 0.5 to 5 nm in size, where the metal is more distributed over the complex, giving it a relatively uniform density over its extent. No aggregation is apparent.
Magnetic measurements of a water solution of the cobalt complexes show the magnetic field, M, vs. magnetic field strength, H, to be a straight line with a shallow slope up to 13,000 Gauss, giving no indication of ferromagnetism or superparamagnetism. The molar susceptibility of the material is low, less than about 0.02 (cgs units), in the range of cobalt ions in solution. All of these data are consistent with organometallic complexes where the metal is not highly condensed into a central core. The complexes are dark brown in color and ultraviolet-visible spectroscopy shows a spectrum that decrements from high absorbtion at 240 nm (the shortest wavelength measured) to low absorbtion at 600 nm, with peaks or shoulders at approximately 380 and 450 nm; one form shows a shoulder at about 364 nm. Larger cobalt and nickel complexes are also described that are orange or red in color, and these have peaks or shoulders at longer wavelengths, about 520 to 540 nm. If dried or precipitated by addition of base, the resulting particulates exhibit motion in an inhomogeneous magnetic field. When stored in water at room temperature, there is no apparent change in properties for the cobalt complexes over several months. Not only is the material highly water soluble, but it is not “sticky” and does not adhere to glass surfaces or proteins such as albumin. The organic peptide component allows covalent conjugation to antibodies or other molecules. The complexes appeared to be pure in that they ran as a single peak on a gel filtration column in aqueous buffer, and ran as a single spot on a TLC (thin layer chromatography) plate in 50:50 methanol:water. These unusual characteristics distinguish this new magnetic material from others previously described.
Advantages
The unique properties of this new class of magnetic materials make them ideal for many applications. The high water solubility is useful for biological applications, which are predominantly aqueous solution based. The stability is a valuable asset to almost all uses.
The non-aggregation of particles or complexes is particularly important to their use. Once material aggregates, its properties
Farrell Kevin M.
Nazario-Gonzalez Porfirio
Pierce Atwood
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