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US5260050A
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Methods and compositions for magnetic resonance imaging comprising superparamagnetic ferromagnetically coupled chromium complexes
Assignee: Abeona Therapeutics Inc
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Filing: 1990-01-11
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Granted: 1993-11-09
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Expires: 2010-01-11
Abstract
Abstract Improved compositions and methods for selective access to tumor regions (or other regions of abnormal endothelial properties). This capability provides powerful contrast-enhancement agents for nuclear magnetic resonance imaging. A polyatomic complex which includes intramolecular ferromagnetic coupling between metal atoms is associated with a polymer or microsphere carrier matrix which will bind to endothelial determinants. A solution containing this carrier complex is injected into a human (or other) body to be imaged. The carrier complex will preferentially extravasate at locations where the blood vessel walls have increased porosity or microvascular surface changes, and especially at tumor sites. Thus, the changes in relaxation time induced by the presence of the carrier complex will provide a high-gain marker for magnetic resonance imaging. Multiple superparamagnetic polyatomic complexes are described, including novel complexes which include acetate and glycinate bridging ligands with a polyatomic metal-atom-complex core.
Inventors
- 👤 David F. Ranney
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 19:56
CPC Classifications
G; G01; G01R; G01R33/00; G01R33/20; G01R33/44; G01R33/48; G01R33/54; G01R33/56; G01R33/5601; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/56; A61K47/61; A61K47/69; A61K47/6921; A61K47/6927; A61K47/6929; A61K47/6931; A61K47/6939; A61K49/00; A61K49/06; A61K49/08; A61K49/085; A61K49/10; A61K49/12; A61K49/126; A61K49/128; A61K49/18; A61K49/1818; A61K49/1821; A61K49/1824; A61K49/1827; A61K49/1851; A61K49/1863; Y; Y10; Y10S; Y10S436/00; Y10S436/806; Y10S977/00; Y10S977/70; Y10S977/701; Y10S977/702; Y10S977/705; Y10T; Y10T436/00; Y10T436/24
Claims Analysis
Total Claims: 34
Claim 1
Independent Claim
133 words
A composition of matter comprising a superparamagnetic polyatomic metal atom complex, containing plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled, and including bridging ligands bound to said paramagnetic metal atoms, said polyatomic metal complex consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands, said polyatomic complex being bound to or associated with: a biocompatible and at least substantially water-soluble anionic carbohydrate, oligosaccharide, polysaccharide, or glycosaminoglycan carrier; said carrier having repeating hydrophilic units which contain covalently bound available reactive groups selected from the group consisting of hydroxyl, carbonyl, aldehyde, carboxylate, sulfate, phosphate and amine groups, wherein said polyatomic metal atom complex is in a molar ratio to individual repeating units of said carrier of between about 1:2 and about 1:25.
Claim 2
Dependent Claim
133 words
A composition of matter comprising a superparamagnetic polyatomic metal atom complex, containing plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled, and including bridging ligands bound to said paramagnetic metal atoms, said polyatomic metal complex consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands, said polyatomic complex being bound to or associated with: a biocompatible and at least substantially water-soluble anionic carbohydrate, oligosaccharide, polysaccharide, or glycosaminoglycan carrier; said carrier having repeating hydrophilic units which contain covalently bound available reactive groups selected from the group consisting of hydroxyl, carbonyl, aldehyde, carboxylate, sulfate, phosphate and amine groups, wherein said polyatomic metal atom complex is in a molar ratio to individual repeating units of said carrier of between about 1:2 and about 1:25.
Claim 3
Dependent Claim
19 words
The composition of claim 1 defined further, wherein said carrier is complementary to determinants of vertebrate endothelia or epithelia.
Claim 4
Dependent Claim
27 words
The composition of claim 1, defined further as an in vivo diagnostic agent for enhancing internal images or shifting internal spectra arising from induced magnetic resonance signals.
Claim 5
Dependent Claim
19 words
The composition of claim 1, wherein said carrier has a molecular weight between about 1,000 and about 200,000 Daltons.
Claim 6
Dependent Claim
19 words
The composition of claim 1, wherein said carrier has a molecular weight between about 15,000 and about 45,000 Daltons.
Claim 7
Dependent Claim
25 words
The composition of claim 1, wherein said polyatomic metal atom complex is bound to said carrier noncovalently by a strong ionic, paired-ion or charge interaction.
Claim 8
Dependent Claim
58 words
The composition of claim 6, wherein said strong interaction is by chemical coordination or chelation binding of said polyatomic metal atom complex to one or more of said reactive groups of said polymer, each site of said coordination or chelation binding, on said carrier, having a coordination number or ionic charge number of between 2 and 10 inclusive.
Claim 9
Dependent Claim
17 words
The composition of claim 1, wherein said polyatomic metal atom complex is covalently conjugated to said carrier.
Claim 10
Dependent Claim
31 words
The composition of claim 8, wherein said covalent conjugation of said polyatomic metal atom complex to said carrier is by a metal-oxide bond or a direct metal bond to said carrier.
Claim 11
Dependent Claim
31 words
The composition of claim 1, wherein said carrier has a molecular size of less than about twelve nanometers, and said carrier contains less than about 5% (w/w) cross-linked or microaggregated species.
Claim 12
Dependent Claim
45 words
The composition of claim 1 wherein said water-soluble carrier is dextran, dextran sulfate, carboxymethyl dextran, dicarboxyethyl dextran, succinylated dextran, diethylenetriaminepentaacetate-dextran, dicarboxyethylhydroxyethyl starch, carboxymethylhydroxyethyl starch, succinylated hydroxyethyl starch, diethylenetriamine pentaacetate-starch, heparin, heparan sulfate, dermatan sulfate, pentosan polysulfate, dicarboxyethyl heparin, a heparin fragment, succinylated heparin, or diethylenetriaminepentaacetate-heparin.
Claim 13
Dependent Claim
35 words
The composition of claim 1, wherein said bridging ligands are acetate groups and said polyatomic metal atom complex consists essentially of Cr 4 S(O 2 CCH 3 ) 8 (H 2 O) 4 +2 .
Claim 14
Dependent Claim
86 words
The composition of claim 1, wherein said polyatomic metal atom complex has the formula (Cr 4 SR n C m ), where R is a bridging ligand of formate, formaldehyde, glutaraldehyde, acetate, glycinate, succinate, acetylacetonate, malonate, propionate, glutarate, hydroxamate, oxalate, 2-bromoacetate, 2-sulfoethanoate, thiolacetate or thioglycolate; n is the number of R groups per metal atom complex, numbering between 4 and 12; C is a stabilizing counterion selected from the group consisting of water, halide, sulfate, nitrate, carboxylate, and phosphate; and m is between 1 and 2n.
Claim 15
Dependent Claim
48 words
The composition of claim 13 defined further, wherein said bridging is a combination of acetate and glycinate groups at a molar ratio of between about 1 and about 3 glycinates per polyatomic complex and amino groups of said glycinate assist in binding said polyatomic complex to said carrier.
Claim 16
Dependent Claim
16 words
The composition of claim 1, wherein said carrier consists essentially of heparin, or a heparin fragment.
Claim 17
Dependent Claim
18 words
The composition of claim 1, wherein said carrier has a molecular weight of between 15,000 and 26,000 Daltons.
Claim 18
Dependent Claim
38 words
The composition of claim 1, wherein said polyatomic metal atom complex is Cr 4 S(O 2 CCH 3 ) 8 , and said carrier consists essentially of dextran, carboxymethyl dextran, dicarboxyethyldextran, succinylated dextran, diethylenetriamine pentaacetate-dextran or dextran sulfate.
Claim 19
Dependent Claim
41 words
The composition of claim 1, wherein said polyatomic metal atom complex is Cr 4 S(O 2 CCH 3 ) 8 , and said carrier consists essentially of hydroxyethyl starch, carboxymethyl hydroxyethyl starch, dicarboxyethyl hydroxyethyl starch, succinylated hydroxyethyl starch or diethylenetriamine pentaacetate-starch.
Claim 20
Dependent Claim
37 words
The composition of claim 2, wherein said polyatomic metal atom complex is Cr 4 S(O 2 CCH 3 ) 8 , and said carrier consists essentially of heparin, dicarboxyethyl heparin, carboxymethyl heparin, succinylated heparin or diethylenetriamine pentaacetate-heparin.
Claim 21
Dependent Claim
28 words
The composition of claim 1, wherein said polyatomic metal atom complex and said carrier are formulated as microspheres with a diameter between 0.1 micrometers and about 250 micrometers.
Claim 22
Dependent Claim
55 words
The composition of claim 20, wherein said microspheres have a diameter between about 0.1 micrometer and about 4.0 micrometers, and said polyatomic metal atom cluster consists essentially of (Cr 4 S(O 2 CCH 3 ) 8 (H 2 O) 4 ) +2 bound to diethylenetriamine pentaacetate-dextran, diethylenetriamine pentaacetate-hydroxyethyl starch, heparin, dextran sulfate or pentosan polysulfate.
Claim 23
Independent Claim
193 words
A method for magnetic resonance imaging, comprising the steps of: identifying a living vertebrate animal to be imaged; introducing into the blood stream or body cavity of said animal a diagnostically effective amount of a diagnostic imaging agent comprising an at least substantially water-soluble anionic carrier with a molecular weight of greater than about 1,000 Daltons, and also includes plural superparamagnetic polyatomic metal atom complexes associated with said carrier, each of polyatomic metal atom complexes including plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled metal, said polyatomic metal complexes consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands; applying to said animal a strong magnetic field which includes a gradient; and applying to at least a portion of said animal an electromagnetic perturbation field at a radio frequency corresponding to a resonant frequency of a predetermined atomic nucleus at a magnetic field strength which falls within a range of field strengths applied to said animal by said strong magnetic field, and measuring radio frequency emissions to define a spatial map of magnetic resonance characteristics within tissues of said animal.
Claim 24
Independent Claim
193 words
A method for magnetic resonance imaging, comprising the steps of: identifying a living vertebrate animal to be imaged; introducing into the blood stream or body cavity of said animal a diagnostically effective amount of a diagnostic imaging agent comprising an at least substantially water-soluble anionic carrier with a molecular weight of greater than about 1,000 Daltons, and also includes plural superparamagnetic polyatomic metal atom complexes associated with said carrier, each of polyatomic metal atom complexes including plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled metal, said polyatomic metal complexes consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands; applying to said animal a strong magnetic field which includes a gradient; and applying to at least a portion of said animal an electromagnetic perturbation field at a radio frequency corresponding to a resonant frequency of a predetermined atomic nucleus at a magnetic field strength which falls within a range of field strengths applied to said animal by said strong magnetic field, and measuring radio frequency emissions to define a spatial map of magnetic resonance characteristics within tissues of said animal.
Claim 25
Dependent Claim
19 words
The method of claim 22, wherein said carrier molecule has a molecular weight of about 15,000 to 45,000 Daltons.
Claim 26
Dependent Claim
16 words
The method of claim 22, wherein said carrier consists essentially of heparin or a heparin fragment.
Claim 27
Dependent Claim
51 words
The method of claim 22, wherein said carrier consists essentially of heparin, or a heparin fragment, and the size of said polymeric compound is less than about twelve nanometers, and said superparamagnetic polyatomic complex consists essentially of Cr 4 S(O 2 CCH 3 ) 8 (H 2 O) 4 +2 .
Claim 28
Dependent Claim
27 words
The method of claim 22, wherein said superparamagnetic polyatomic complex consists essentially of Cr 4 S(O 2 CCH 3 ) 8 (H 2 O) 4 +2 .
Claim 29
Dependent Claim
145 words
A composition of matter comprising a superparamagnetic polyatomic metal atom complex, containing plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled, and including bridging ligands bound to said paramagnetic metal atoms, said polyatomic metal complex consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands, said polyatomic complex being bound to or associated with: a biocompatible and at least substantially water-soluble anionic carbohydrate, oligosaccharide, polysaccharide, or glycosaminoglycan carrier; said carrier having repeating hydrophilic units which contain covalently bound available reactive groups selected from the group consisting of hydroxyl, carbonyl, aldehyde, carboxylate, sulfate, phosphate and amine groups, wherein said carrier is complementary to determinants of vertebrate endothelia or epithelia, wherein said polyatomic metal atom complex is in a molar ratio to individual repeating units of said carrier of between about 1:2 and about 1:25.
Claim 30
Dependent Claim
145 words
A composition of matter comprising a superparamagnetic polyatomic metal atom complex, containing plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled, and including bridging ligands bound to said paramagnetic metal atoms, said polyatomic metal complex consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands, said polyatomic complex being bound to or associated with: a biocompatible and at least substantially water-soluble anionic carbohydrate, oligosaccharide, polysaccharide, or glycosaminoglycan carrier; said carrier having repeating hydrophilic units which contain covalently bound available reactive groups selected from the group consisting of hydroxyl, carbonyl, aldehyde, carboxylate, sulfate, phosphate and amine groups, wherein said carrier is complementary to determinants of vertebrate endothelia or epithelia, wherein said polyatomic metal atom complex is in a molar ratio to individual repeating units of said carrier of between about 1:2 and about 1:25.
Claim 31
Dependent Claim
120 words
A composition of matter comprising a superparamagnetic polyatomic metal atom complex, containing plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled, and including bridging ligands bound to said paramagnetic metal atoms, said polyatomic metal complex consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands, said polyatomic complex being bound to or associated with: a biocompatible and at least substantially water-soluble carbohydrate, oligosaccharide, polysaccharide, or glycosaminoglycan carrier; said carrier having repeating hydrophilic units which contain covalently bound available reactive carboxylate or sulfate groups, wherein said polyatomic metal atom complex is in a molar ratio to individual repeating units of said carrier of between about 1:2 and about 1:25.
Claim 32
Dependent Claim
120 words
A composition of matter comprising a superparamagnetic polyatomic metal atom complex, containing plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled, and including bridging ligands bound to said paramagnetic metal atoms, said polyatomic metal complex consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands, said polyatomic complex being bound to or associated with: a biocompatible and at least substantially water-soluble carbohydrate, oligosaccharide, polysaccharide, or glycosaminoglycan carrier; said carrier having repeating hydrophilic units which contain covalently bound available reactive carboxylate or sulfate groups, wherein said polyatomic metal atom complex is in a molar ratio to individual repeating units of said carrier of between about 1:2 and about 1:25.
Claim 33
Dependent Claim
138 words
A composition of matter comprising a superparamagnetic polyatomic metal atom complex, containing plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled, and including bridging ligands bound to said paramagnetic metal atoms, said polyatomic metal complex consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands, said polyatomic complex being bound to or associated with: a biocompatible and at least substantially water-soluble carbohydrate, oligosaccharide, polysaccharide, or glycosaminoglycan carrier; said carrier having repeating hydrophilic units which contain covalently bound available reactive groups selected from the group consisting of carboxylate and sulfate, wherein said carrier is complementary to determinants of vertebrate endothelia or epithelia, wherein said polyatomic metal atom complex is in a molar ratio to individual repeating units of said carrier of between about 1:2 and about 1:25.
Claim 34
Dependent Claim
138 words
A composition of matter comprising a superparamagnetic polyatomic metal atom complex, containing plural paramagnetic metal atoms which are intramolecularly ferromagnetically coupled, and including bridging ligands bound to said paramagnetic metal atoms, said polyatomic metal complex consisting essentially of four Cr(III) atoms which are bound to a central tetrahedral sulfur atom and are octahedrally coordinated by bridging ligands, said polyatomic complex being bound to or associated with: a biocompatible and at least substantially water-soluble carbohydrate, oligosaccharide, polysaccharide, or glycosaminoglycan carrier; said carrier having repeating hydrophilic units which contain covalently bound available reactive groups selected from the group consisting of carboxylate and sulfate, wherein said carrier is complementary to determinants of vertebrate endothelia or epithelia, wherein said polyatomic metal atom complex is in a molar ratio to individual repeating units of said carrier of between about 1:2 and about 1:25.
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