EP0361960A2
Expired / Lapsed
EP
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Methods and compositions for magnetic resonance imaging
Assignee: Individual
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Filing: 1989-09-29
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Granted: —
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Expires: 2009-09-29
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
EP
Data Source
google_patents
Last Synchronized
2026-11-03 07:43
CPC Classifications
G; G01; G01R; G01R33/00; G01R33/20; G01R33/44; G01R33/48; G01R33/54; G01R33/56; G01R33/5601; A; A61; A61K; A61K49/00; A61K49/06; A61K49/08; A61K49/085; A61K49/10; A61K49/12; A61K49/126
Claims Analysis
Total Claims: 29
Claim 1
Independent Claim
118 words
A composition of matter comprising: a superparamagnetic polyatomic complex , containing plural paramagnetic metal atoms mutually ferromagnetically coupled, and including multiple bridging ligand groups which are bound to ones of said paramagnetic atoms, said polyatomic complex being bound to or associated with: a biocompatible, clearable carrier comprising a substantially completely water-soluble polymer which is native or modified carbohydrate, oligosaccharide, polysaccharide, glycosaminoglycan, or structurally analogous synthetic polymers; said carrier having repeating hydrophilic monomeric units which contain covalently bound available reactive groups selected from the group consisting of one or more of: hydroxyl, carbonyl, aldehyde, carboxylate, sulfate, phosphate and amine groups, singly or in combination; wherein the molar ratio of said polyatomic complex to said carrier is at least 10:1.
Claim 2
Dependent Claim
118 words
A composition of matter comprising: a superparamagnetic polyatomic complex , containing plural paramagnetic metal atoms mutually ferromagnetically coupled, and including multiple bridging ligand groups which are bound to ones of said paramagnetic atoms, said polyatomic complex being bound to or associated with: a biocompatible, clearable carrier comprising a substantially completely water-soluble polymer which is native or modified carbohydrate, oligosaccharide, polysaccharide, glycosaminoglycan, or structurally analogous synthetic polymers; said carrier having repeating hydrophilic monomeric units which contain covalently bound available reactive groups selected from the group consisting of one or more of: hydroxyl, carbonyl, aldehyde, carboxylate, sulfate, phosphate and amine groups, singly or in combination; wherein the molar ratio of said polyatomic complex to said carrier is at least 10:1.
Claim 3
Dependent Claim
24 words
The composition of Claim 1 defined further, wherein said reactive groups of said carrier are chemically complementary to determinants of vertebrate endothelia or epithelia.
Claim 4
Dependent Claim
30 words
The composition of Claim 1, defined further as an in vivo diagnostic agent with the capacity to enhance internal images or shift internal spectra arising from induced magnetic resonance signals.
Claim 5
Dependent Claim
18 words
The composition of Claim 1, wherein said carrier has a molecular weight between about 15,000 and 40,000 Daltons.
Claim 6
Dependent Claim
74 words
The composition of Claim 1, wherein said polyatomic metal atom complexes are bound to said carrier noncovalently by a strong ionic, paired-ion or charge interaction, and wherein said strong ionic, paired-ion or charge interaction is by chemical coordination or chelation binding of said polyatomic metal atom complex by ones of said reactive groups of said polymer, each site of said coordination or chelation binding having a coordination number of between 2 and 10 inclusive.
Claim 7
Dependent Claim
60 words
The composition of Claim 1, wherein the molecular diameter of said carrier is less than about twelve nanometers, and said polyatomic metal atoms complex is in a molar ratio to said monomeric units of said carrier of between about 1:2 and about 1:8, and said carrier contains less than about 5% (w/w) cross-linked or microaggregated species, all of low toxicity.
Claim 8
Dependent Claim
58 words
The composition of Claim 1, wherein said water-soluble polymer of said carrier comprises one or more of the following: dextran, dextran sulfate, diethylaminoethyl dextran, carboxymethyl dextran, dicarboxyethyl dextran, succinylated dextran, diethylenetriaminepentaacetate-dextran, hydroxyethyl starch, dicarboxyethylhydroxyethyl starch, carboxymethylhydroxyethyl starch, succinylated hydroxyethyl starch or diethylenetriamine pentaacetate-starch, heparin, heparin sulfate, dermatan sulfate, pentosan polysulfate, dicarboxyethyl heparin, succinylated heparin or diethylenetriaminepentaacetate-heparin, and CARBETIMER™.
Claim 9
Dependent Claim
35 words
The composition of Claim 1, wherein said paramagnetic metal atoms include one or more selected from the group consisting of: chromium, copper, manganese, iron, platinum, cobalt, vanadium, molybdenum, tungsten, gadolinium, erbium, dysprosium, europium, and holmium.
Claim 10
Dependent Claim
95 words
The composition of Claim 1, wherein said superparamagnetic polyatomic complex has the formula (Cr₄SR n C m ), where R is a bridging ligand including one or more 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 or one or more of the following ions: halide, sulfate, nitrate, carboxylate, and phosphate; and m is between 1 and 2n.
Claim 11
Dependent Claim
44 words
The composition of Claim 1 defined further, wherein said bridging ligands comprise a combination of acetate and glycinate groups at a molar ratio of between about 1 and 3 glycinates per polyatomic cluster, and amino groups of said glycinate assist binding to said carrier.
Claim 12
Dependent Claim
28 words
The composition of Claim 1, wherein said polyatomic metal atom complex comprises a water-soluble water-stable compound in which said metal atoms comprise gadolinium atoms bound to acetate groups.
Claim 13
Dependent Claim
42 words
The composition of Claim 22, 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 (Cr₄S(O₂CCH₃)₈(H₂O)₄)⁺² bound to diethylenetriamine pentaacetate-dextran, diethylenetriamine pentaacetate-hydroxyethyl starch, heparin, dextran sulfate or pentosan polysulfate.
Claim 14
Dependent Claim
109 words
A composition of matter comprising: a metal atom complex or coordinate, bound by chelation or coordination to: a biocompatible, clearable carrier comprising a substantially completely water-soluble polymer selected from the group consisting of: native or modified carbohydrate, oligosaccharide, polysaccharide, glycosaminoglycan, or structurally analogous synthetic polymers; said carrier having repeating hydrophilic monomeric units which contain covalently bound available reactive groups; wherein said metal atom complex is bound to said carrier by coordination or chelation binding of said metal atom complex by ones of said reactive groups of said polymer, each site of said coordination or chelation binding, on said carrier, having a coordination number of between 2 and 10 inclusive.
Claim 15
Dependent Claim
109 words
A composition of matter comprising: a metal atom complex or coordinate, bound by chelation or coordination to: a biocompatible, clearable carrier comprising a substantially completely water-soluble polymer selected from the group consisting of: native or modified carbohydrate, oligosaccharide, polysaccharide, glycosaminoglycan, or structurally analogous synthetic polymers; said carrier having repeating hydrophilic monomeric units which contain covalently bound available reactive groups; wherein said metal atom complex is bound to said carrier by coordination or chelation binding of said metal atom complex by ones of said reactive groups of said polymer, each site of said coordination or chelation binding, on said carrier, having a coordination number of between 2 and 10 inclusive.
Claim 16
Dependent Claim
34 words
The composition of matter of Claim 13, wherein said metal atom complex includes a therapeutic agent which is a metal-atom-containing antitumor drug, cis-dichlorodiamine platinum or other platinum complexes and coordinates, or boron or boroleptics.
Claim 17
Dependent Claim
31 words
the composition of matter of Claim 13, wherein said metal atom complex includes cis-dichlorodiamine platinum or other therapeutic platinum coordinates, and wherein said polymer of said carrier is heparin or diethylenetriaminepentaacetate-dextran.
Claim 18
Dependent Claim
83 words
A composition of matter comprising: a metal atom complex or coordinate, bound to: a biocompatible, clearable carrier comprising a substantially completely water-soluble polymer selected from the group consisting of: native or modified carbohydrate, oligosaccharide, polysaccharide, glycosaminoglycan, or structurally analogous synthetic polymers; said carrier having repeating hydrophilic monomeric units which contain covalently bound available reactive groups which are complementary to determinants of vertebrate epithelia or endothelia; and wherein said carrier has a molecular weight which substantially always falls between about 15,000 and 40,000 Daltons.
Claim 19
Dependent Claim
83 words
A composition of matter comprising: a metal atom complex or coordinate, bound to: a biocompatible, clearable carrier comprising a substantially completely water-soluble polymer selected from the group consisting of: native or modified carbohydrate, oligosaccharide, polysaccharide, glycosaminoglycan, or structurally analogous synthetic polymers; said carrier having repeating hydrophilic monomeric units which contain covalently bound available reactive groups which are complementary to determinants of vertebrate epithelia or endothelia; and wherein said carrier has a molecular weight which substantially always falls between about 15,000 and 40,000 Daltons.
Claim 20
Independent Claim
181 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 diagnostic imaging or spectral enhancement or spectral shift agent comprising a hydrophilic polymeric compound which comprises a carrier molecule with a molecular weight of greater than about 15,000 Daltons, and also includes multiple polyatomic metal atom complexes associated with each said carrier molecule, each of polyatomic metal atom complexes including multiple paramagnetic metal atoms which are magnetically coupled to collectively render each said polyatomic metal atom complex superparamagnetic; 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 generally corresponding to a resonant frequency of a predetermined atomic nucleus at a magnetic field strength which falls within the range of field strengths applied to said animal by said strong magnetic field, and measuring the radio frequency emissions to define a spatial map of magnetic resonance characteristics within tissues of said animal.
Claim 21
Independent Claim
181 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 diagnostic imaging or spectral enhancement or spectral shift agent comprising a hydrophilic polymeric compound which comprises a carrier molecule with a molecular weight of greater than about 15,000 Daltons, and also includes multiple polyatomic metal atom complexes associated with each said carrier molecule, each of polyatomic metal atom complexes including multiple paramagnetic metal atoms which are magnetically coupled to collectively render each said polyatomic metal atom complex superparamagnetic; 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 generally corresponding to a resonant frequency of a predetermined atomic nucleus at a magnetic field strength which falls within the range of field strengths applied to said animal by said strong magnetic field, and measuring the radio frequency emissions to define a spatial map of magnetic resonance characteristics within tissues of said animal.
Claim 22
Independent Claim
107 words
A method for selective hysteresis heating, comprising the steps of: identifying a living vertebrate animal to be heated; introducing into the blood stream or body cavity of said animal an agent comprising a hydrophilic polymeric compound which comprises a carrier molecule with a molecular weight of greater than about 15,000 Daltons, and also includes multiple polyatomic metal atom complexes associated with each said carrier molecule, each of polyatomic metal atom complexes includng multiple paramagnetic metal atoms which are mutually ferromagnetically coupled to collectively render each said polyatomic metal atom complex superparamagnetic; and applying radio frequency energy to said animal at a relatively high field intensity and energy.
Claim 23
Independent Claim
107 words
A method for selective hysteresis heating, comprising the steps of: identifying a living vertebrate animal to be heated; introducing into the blood stream or body cavity of said animal an agent comprising a hydrophilic polymeric compound which comprises a carrier molecule with a molecular weight of greater than about 15,000 Daltons, and also includes multiple polyatomic metal atom complexes associated with each said carrier molecule, each of polyatomic metal atom complexes includng multiple paramagnetic metal atoms which are mutually ferromagnetically coupled to collectively render each said polyatomic metal atom complex superparamagnetic; and applying radio frequency energy to said animal at a relatively high field intensity and energy.
Claim 24
Independent Claim
78 words
A method of magnetic resonance imaging, characterised in that the body or material to be imaged contains an agent comprising a hydrophilic polymeric compound which comprises a carrier molecule with a molecular weight of greater than about 15,000 Daltons, and also includes multiple polyatomic metal atom complexes associated with each said carrier molecule, each of polyatomic metal atom complexes including multiple paramagnetic metal atoms which are magnetically coupled to collectively render each said polyatomic metal atom complex superparamagnetic.
Claim 25
Independent Claim
78 words
A method of magnetic resonance imaging, characterised in that the body or material to be imaged contains an agent comprising a hydrophilic polymeric compound which comprises a carrier molecule with a molecular weight of greater than about 15,000 Daltons, and also includes multiple polyatomic metal atom complexes associated with each said carrier molecule, each of polyatomic metal atom complexes including multiple paramagnetic metal atoms which are magnetically coupled to collectively render each said polyatomic metal atom complex superparamagnetic.
Claim 26
Dependent Claim
87 words
A method according to claim 19, characterised by applying to said body or material a strong magnetic field which includes a gradient and applying to at least a portion of said body or material an eletromagnetic perturbation field at a radio frequency generally corresponding to a resonant frequency of a predetermined atomic nucleus at a magnetic field strength which falls within the range of field strengths applied by said strong magnetic field, and measuring the radio frequency emissions to define a spatial map of magnetic resonance characteristics.
Claim 27
Independent Claim
79 words
A method of radio frequency heating, characterised in that the material or body to be heated contains an agent comprising a hydrophilic polymeric compound which comprises a carrier molecule with a molecular weight of greater than about 15,000 Daltons, and also includes multiple polyatomic metal atom complexes associated with each said carrier molecular, each of polyatomic metal atom complexes including multiple paramagnetic metal atoms which are mutually ferromagnetically coupled to collectively render each said polyatomic metal atom complex superparamagnetic.
Claim 28
Independent Claim
79 words
A method of radio frequency heating, characterised in that the material or body to be heated contains an agent comprising a hydrophilic polymeric compound which comprises a carrier molecule with a molecular weight of greater than about 15,000 Daltons, and also includes multiple polyatomic metal atom complexes associated with each said carrier molecular, each of polyatomic metal atom complexes including multiple paramagnetic metal atoms which are mutually ferromagnetically coupled to collectively render each said polyatomic metal atom complex superparamagnetic.
Claim 29
Dependent Claim
28 words
The composition of any of claims 1 to 16 when prepared for use in or in connection with a surgical, therapeutical or diagnostic method on a living body.
References Cited (Backward Citations)
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