CA1268208A - Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging - Google Patents
Magnetic micro-particles as contrast agents in nuclear magnetic resonance imagingInfo
- Publication number
- CA1268208A CA1268208A CA000485587A CA485587A CA1268208A CA 1268208 A CA1268208 A CA 1268208A CA 000485587 A CA000485587 A CA 000485587A CA 485587 A CA485587 A CA 485587A CA 1268208 A CA1268208 A CA 1268208A
- Authority
- CA
- Canada
- Prior art keywords
- tissue
- magnetic
- micro
- particles
- image
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nanotechnology (AREA)
- Epidemiology (AREA)
- Radiology & Medical Imaging (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
NMR imaging of animal tissue is improved by a contrast-enhancing agent in the form of magnetic micro-particles comprising magnetic material coupled to a substance having binding affinity for the target tissue.
NMR imaging of animal tissue is improved by a contrast-enhancing agent in the form of magnetic micro-particles comprising magnetic material coupled to a substance having binding affinity for the target tissue.
Description
MAGNETIC MICRO-PARTICLES AS CONTRAST
AGENTS IN NUCLE M MAGNETIC RESONANCE IMAGING
BY
TRUMAN BROWN
BACKGROUND OF THE INVENTION
The pre~ent invention relates to an improvement in nuclear magnetic resonance (NMR) imaging and in particular to the use of tis3ue specific magnetic micro-particle~ a3 contrast enhancing agents in NMR
imaging.
NMR spectroscopy has been used for a number of years as an analytical technique for organic chemical ~tructure determinations. This technique is ba~ed on the magnetic properties of nuclei containing odd numbers of proton3 and neutrons. Nuclei po~sess an angular momentum which, in conjunction with the charge thereof, produces a magnetic field, the axi~ of which i9 directed along the spin axis of each nucleus. The application of a magnetic field to the nuclei cause alteration of the natural spin direceions, which become aligned either with or against the applied field. The nuclei also prece~s or rotate about their axe3 at a characteristic frequency.
The rotational angle may be changed by abYorption of electro-magnetic energy through a phenomen known as resonance, which involve~ impres3ing on the nuclei a 3econd magnetic field of appropriate frequency to match that of their normal precession. When the ~econd magnetic field i3 interrupted or terminated, the nuclei return to their initial precession state, generating radio signals having a detectable decay rate or relaxation time. The ~pin-lattice relaxation time (Tl) is the rate at which spin energy is converted into ~2~
~ 2 --thermal energy and transferred to the aggregate of atoms or molecules under ~tudy. The qpin-spin relaxatlon time (T2) is the rate at which spin energy of nuclei in a high energy state is transferred to neighboring nuclei.
The radio signal generated by any given nucleus will have a characteri~tic relaxation time depending on its chemical environment.
More recently, NMR technique has been further developed and refined to provide a potentially valuable diagnostic to~l, enabling visualization of body tissue.
~It is possible to distinguish between abnormal and normal tissue, e.g. a lesion and surrounding normal tis~ue, on the basis of differences in spin-lattice and/or ~pin-~pin relaxation times. Remarkably clear images are obtainable that can aid in the characterization of pathologic or physiologic proceqses within various organs, including the brain, kidneys, and heart.
In carrying out NMR imaging, a suitable radio frequency pulse sequence ~saturation-recovery, inversion-recovery or spin-echo) is used to induce a signal in nearby receiver coils The signal's exact frequency, phase and strength are determined through a mathematical function known as a Fourier transform. The signals are a3~iqned shading intensity enabling a computer to convert the re~ults into an image of the targeted organ ~ystem.
There have been numerous reports over the laqt several year~ that contrast agents may contribute significantly to the diagnostic utility of NMR imaging.
Contrast agents enhance the difference in signal observed between magnetically similar but histologlcally diqsimilar ti~sue, giving images oE quperior contrast that prbvide maximum diagnostic information.
o~
The mechanism of action of the specific magnetic micro-particles u~ed as NMR contrast enhancing agents in the present invention is to ~e distinguished from iodinated contrast media typically used in radiography.
Magnetic micro-particles alter the magnetic environment in the target organ system, ~o a~ to enhance proton relaxation by decreasing the spin-spin relaxation time.
Contrast enhancement is thus produced indirectly by the effect of the magnetic micro-particle on neighborlng nuclei. On the other hand, iodinated contrast media used i~n radiography generally have a high electron density and effect contrast directly by absorption of x-rays. Such agentR generally do not affect proton NMR signals, and therefore, do not function as contrast media in NMR
imaging. Moreover, unlike iodinated contrast media, the NMR contra~t agents described herein are not observed directly on the image, since the magnetic effect produced on neighboring nuclei is the mean~ of contrast enhancement.
In order for a substance to be acceptable a~ an NMR
contrast-enhancing agent a number of critica must be `
satisfied. The contrast agent should be easily manufactured from relatively inexpensive ~tarting materials, chemically ~table and readily stored in a form suitable for administration. More importantly, the contra~t agent should have a reasonably strong influence on proton relaxation time~ in relatively low concentrations, but be essentially free of tox~c effects or other undesirable side effects in appropriate dosages.
In addition, the contrast agent should be tlssue-specific, i.e. permit selective ti~sue targetting.
Furthermore, the contra~t agent must remain stable in vivo and`ultimately be deactivated or excreted.
8~0~
SUMMARY OF T~E INVENTION
In accordance with the present invention there is provided an improved method for producing an image of animal ti~sue by nuclear magnetic re~onance imaging, which compri~es binding to the tissue whose image i~
de~ired a magnetic micro-particle comprising magnetic material coupled to a 3ub~tance having binding af~inity for the animal tis~ue, in an amount effective for causing a 3ubstantial reduction in the relaxation time of nearby nuclei, thereby effecting contrast enhancement in the ~e~ulting image. The magnetic material i8 conveniently coupled to the subAtance having binding affinity for the target ti~ue by coating the magnetic material with a bio-compatible polymer ha~ing reactive functional group~
and forming chemical bond~ between the functional groups and the substance having binding affinity for the target ti~sue.
The magnetic micro-particle used a~ a contrast-enhancing agent in the practice of the present invention fulfills all ~he criteria noted above. The contrast agent ls made from commercially available and relatively inexpensive magnetic material~, which are readily coupled to various tis~ue-specific binding substance3 by procedure~ well known to those ~killed in art. Polymer coated magnetic particles are extremely ~table and may be easily readied for administration by coupling to the ~ubstance having binding affinity for the target tis~ue.
The degree of magnetization of the magnetic micro-particles, when magnetically polarized, will cause a ~ubstantial local perturbation to the steady magnetic field applied to the ~arget tis~ue, the detail~ of the perturbation depending on the magnetic material selected and the~particle ~ize thereof. Thi~ high degree of L~6~
magnetization exerts an extremely ~trong influence on nuclear relaxation time. The magnetic effect of this contra~t agent cau~e~ magnetic pha~e perturbation in nuclei up to about 20 micron~ or more removed from the contrast agent, permitting extremely small amount~ of the agent to be u3ed, e.g. on th,e order of one to ten magnetic micro-particles per cell, thus providing a NMR
contra~t agent oE exceptional sensitivity, enabling the detection of the distribution and transfer of neurotransmitter substances iand low level hormone receptor~. The u~e of bio-compatible coating~ on the magnetic particle~ renders them free of toxic or other undersirable side effects. The contra~t agent of the present invention also enable~ selective tissue targeting by rea~on of the coupling thereto of a substance having binding affinity for the target tissue. With regard to deactivation of the contra~t agent, it i3 believed that over time it will be taken up by macrophaqe~ and strored in the body.
The contrast agent of the pre~ent invention may be used to particular advantage in tumor imaging by the u~e of magnetic micro-particle~ comprising magnetic material coupled eO antibody which bind3 specifically to tumor-associated antigen. Other feature~ and advantages of the inYention will become apparent to those skilled in the art from the following detailed descripeion thereof.
DETAILED DESCRIPTION OF THE INVENTION
Various magnetic materials may be used in preparing the magnetic micro-particles employed in the present invention. As used herein, the term ~magnetic materials"
refers to those materials exhibiting ferromagnetism, and include3 materials having a high magnetic su~ceptibity - 6 ~
such that their internal magnetic field~ are on the order of about one thousand gauss. Ferromagnetic material3 useful in the pre~ent invention are characterized by having domains of magnetism which become aligned with an external magnetic field, thus producing a high internal magentic field. Suitable magnetic material includs iron, cobalt, nickel and manganese. Compounds or alloy~
of the~e elements which exhibit ferromagnetism, e.g.
magnetite (Fe304) or Mn-Cu alloy may also be used.
The size of the magnetic micro-particles will depend on the target organ system. In general, the average particle size will be greater than few hundred Angstrom units, but leqs than about one micron.
The substance having tissue-binding affinity that is selected for coupling to the magnetic micro-particles will be determined by the particular tissue whose image is desired. Examples of such substances include antibodies, preferably monoclonal antibodies, neurotransmitters, hormones, matabolite~, enzymes, toxins, and natural or ~ynthetic drugs. Analogues of these substances may also be employed, if desired. As used herein the term "analogue" refers to synthetic materials that elicit a physioloqical response comparable to that of the natural substance.
A~ previously noted, the sub~tance having tissue-binding affinity may be coupled to the magnetic micro-particles according to procedures well known in the art. This may be most conveniently accomplished by providing the magnetic micro-particles with a polymer coating having reactive functional 9rOUpB~ and attachinq the tissue-apecific ~ubstance to the polymer coating by chemical bonding to the functional groups of the polymer.
A polymer coating may be applied to the magnetic material by a redox polymerization proce3s wherein a metal oxide, e.g. magnetite serves as a source of reducing agent in the redox activation system. Such a process i3 describecl in U.S. Patent No. ~,157,323 t*e~ ~e-d~sc~s~rF-uf--~h~ ~e~r-a-t~ ~ i~-t-he-~r~t--~p~lic~ti~_by -Eefer~en~-aff-~h~h-se-t--f-~r-lh-he~e-~-i~ full. Polymer coating~ may also be applied to magnetic substrates according to the procedure described in ~.S. Patent No.
4,070,246. Polymer-coated nnagnetic micro-particles are commercially available from a number of sources.
Bio-compatible polymer~ are preferred for use in the present invention. The term "bio-compatible polymer~ i9 intended to qignify a polymer that doe~ not produce any significant toxic effect or other undesirable effect on the test subject to whom the magnetic micro-particles are administered. Bio-compatible polymers may be either synthetic or naturally occuring, representatiYe examples of such polymers being albumin and polystyrene. In addition to facilitating the coupling of the tissue-specific substance, the bio-compatible polymer coating serves to prevent adverse physiological effect~
caused by the magnetic material and to prevent deterioration of the magnetic material by chemicals present in the environment in which the magnetic micro-particles are u~ed.
The ti~sue-Apecific substance may be coupled to the polymer-coated magnetic material by methods familiar to those ~killed in art, ~uch as by covalent bonding, as noted above, or by ionic or hydrogen bonding. Suitable methods for thi~ purpose are disclosed in the aforementioned U.S. Patent No. 4,157,323.
The presently preferred mode of administration of the magnetic micro-particles is by intravenous injection, although other suitable technique~ for introducing the contrast agent into the area of NM~ imaging examination ~2~
may also be used, if desired.
The dosage at which the magnetic micro-particles i~
admini~tered will vary depending on the test subject and the nature of the ti~sue ~ought to be imaged. While it S i9 contemplated that the pre~ent invention will ultimately be used in NMR imaging of human ti~sue, ~uch use ha3 not yet been undertaken. However, the present invention ha3 considerable utility in NMR imaging of the organ systems of lower animals for differention of normal and pathologic tissue, characterization of pathologic tissue, characterization of physiologic or pathologic phenomena, and the like.
The pulse sequence used in obtaing the NMR image in accordance with the present invention should be one which has high sensitivity to spin-spin relaxation parameters.
Although the scientific principle underlying the present invention has not been thoroughly investigated, and is not completely understood, it i3 believed that the magr.etic micro-particle functions as a ~mall magnetic dipole which produces a magnetic field that causes perturbation of the nuclei of water molecules surrounding the magnetic micro-particles in the tissue under examination. The magnetic field will dissipate by the third power of the distance from the magnetic micro-particle. Thus, aq water molecule~ diffuse through the varying magnetic field cau~ed by the presence of the magnetic micro-particles, their magnetic pha~e is seriously perturbed, causing a ~ubstantial reduction in the apparent ~pin-spin relaxation time, and thereby enhancing contrast in the resultant NMR image.
The procedures for obtaining an image of body tis~ue using NMR are well known to those ~killed in the art.
Basic concepts of NMR imaging are set forth in Kaufman et al (eds.) Nuclear Magnetic Resonance Imaging In Medicine~
New York: Igaku-Shoin, 1981. A number of commercial supplier~ exist for NMR imaging apparatus~
Regarding specific applications, the present invention may be used for imaging tumors. Before carrying out this particular application, however, the primary tumor is removed and the tumor antigen is used for the production of monoclonoal antibodies specific the tumor associated antigen. Thereafter, polymer coated magnetic micro-particles are derivatized with the monoclonal antibody. The derivatized magnetic micro~particles are then administered to the te~t subject and after a time sufficient for the magnetic micro-particles to bind to the tumor a~sociated antigen, the NMR image is obtained. The present invention may also be used in obtaining images of the distribution and transfer of specific neurotran~mitter~ in nervous ti~sue, by coupling a neurotransmitter or a neurotransmitter analogue ~o magnetic micro-particles, which are then administered to the test subject and an NMR image of the nervous tissue i~ obtained. Another application of the present invention is in imaging the interaction between hormones and hormone-binding tissues. In this application the magnetic micro-particle comprises magnetic material coupled to a hormone or hormone analogue which binds specifically to receptors associated with the hormone-binding tissue. The image produced by these and other applications of the pre~ent ~nvention should provide valuable information for diagnosising many dieases.
While certain embodiments of the present invention have been described hereinabove, it i~ not intended to limit the invention to such embodiments, but various modifications and may be made therein and thereto without departing from the spirit and scope of the invention as set forth in the following claims.
AGENTS IN NUCLE M MAGNETIC RESONANCE IMAGING
BY
TRUMAN BROWN
BACKGROUND OF THE INVENTION
The pre~ent invention relates to an improvement in nuclear magnetic resonance (NMR) imaging and in particular to the use of tis3ue specific magnetic micro-particle~ a3 contrast enhancing agents in NMR
imaging.
NMR spectroscopy has been used for a number of years as an analytical technique for organic chemical ~tructure determinations. This technique is ba~ed on the magnetic properties of nuclei containing odd numbers of proton3 and neutrons. Nuclei po~sess an angular momentum which, in conjunction with the charge thereof, produces a magnetic field, the axi~ of which i9 directed along the spin axis of each nucleus. The application of a magnetic field to the nuclei cause alteration of the natural spin direceions, which become aligned either with or against the applied field. The nuclei also prece~s or rotate about their axe3 at a characteristic frequency.
The rotational angle may be changed by abYorption of electro-magnetic energy through a phenomen known as resonance, which involve~ impres3ing on the nuclei a 3econd magnetic field of appropriate frequency to match that of their normal precession. When the ~econd magnetic field i3 interrupted or terminated, the nuclei return to their initial precession state, generating radio signals having a detectable decay rate or relaxation time. The ~pin-lattice relaxation time (Tl) is the rate at which spin energy is converted into ~2~
~ 2 --thermal energy and transferred to the aggregate of atoms or molecules under ~tudy. The qpin-spin relaxatlon time (T2) is the rate at which spin energy of nuclei in a high energy state is transferred to neighboring nuclei.
The radio signal generated by any given nucleus will have a characteri~tic relaxation time depending on its chemical environment.
More recently, NMR technique has been further developed and refined to provide a potentially valuable diagnostic to~l, enabling visualization of body tissue.
~It is possible to distinguish between abnormal and normal tissue, e.g. a lesion and surrounding normal tis~ue, on the basis of differences in spin-lattice and/or ~pin-~pin relaxation times. Remarkably clear images are obtainable that can aid in the characterization of pathologic or physiologic proceqses within various organs, including the brain, kidneys, and heart.
In carrying out NMR imaging, a suitable radio frequency pulse sequence ~saturation-recovery, inversion-recovery or spin-echo) is used to induce a signal in nearby receiver coils The signal's exact frequency, phase and strength are determined through a mathematical function known as a Fourier transform. The signals are a3~iqned shading intensity enabling a computer to convert the re~ults into an image of the targeted organ ~ystem.
There have been numerous reports over the laqt several year~ that contrast agents may contribute significantly to the diagnostic utility of NMR imaging.
Contrast agents enhance the difference in signal observed between magnetically similar but histologlcally diqsimilar ti~sue, giving images oE quperior contrast that prbvide maximum diagnostic information.
o~
The mechanism of action of the specific magnetic micro-particles u~ed as NMR contrast enhancing agents in the present invention is to ~e distinguished from iodinated contrast media typically used in radiography.
Magnetic micro-particles alter the magnetic environment in the target organ system, ~o a~ to enhance proton relaxation by decreasing the spin-spin relaxation time.
Contrast enhancement is thus produced indirectly by the effect of the magnetic micro-particle on neighborlng nuclei. On the other hand, iodinated contrast media used i~n radiography generally have a high electron density and effect contrast directly by absorption of x-rays. Such agentR generally do not affect proton NMR signals, and therefore, do not function as contrast media in NMR
imaging. Moreover, unlike iodinated contrast media, the NMR contra~t agents described herein are not observed directly on the image, since the magnetic effect produced on neighboring nuclei is the mean~ of contrast enhancement.
In order for a substance to be acceptable a~ an NMR
contrast-enhancing agent a number of critica must be `
satisfied. The contrast agent should be easily manufactured from relatively inexpensive ~tarting materials, chemically ~table and readily stored in a form suitable for administration. More importantly, the contra~t agent should have a reasonably strong influence on proton relaxation time~ in relatively low concentrations, but be essentially free of tox~c effects or other undesirable side effects in appropriate dosages.
In addition, the contrast agent should be tlssue-specific, i.e. permit selective ti~sue targetting.
Furthermore, the contra~t agent must remain stable in vivo and`ultimately be deactivated or excreted.
8~0~
SUMMARY OF T~E INVENTION
In accordance with the present invention there is provided an improved method for producing an image of animal ti~sue by nuclear magnetic re~onance imaging, which compri~es binding to the tissue whose image i~
de~ired a magnetic micro-particle comprising magnetic material coupled to a 3ub~tance having binding af~inity for the animal tis~ue, in an amount effective for causing a 3ubstantial reduction in the relaxation time of nearby nuclei, thereby effecting contrast enhancement in the ~e~ulting image. The magnetic material i8 conveniently coupled to the subAtance having binding affinity for the target ti~ue by coating the magnetic material with a bio-compatible polymer ha~ing reactive functional group~
and forming chemical bond~ between the functional groups and the substance having binding affinity for the target ti~sue.
The magnetic micro-particle used a~ a contrast-enhancing agent in the practice of the present invention fulfills all ~he criteria noted above. The contrast agent ls made from commercially available and relatively inexpensive magnetic material~, which are readily coupled to various tis~ue-specific binding substance3 by procedure~ well known to those ~killed in art. Polymer coated magnetic particles are extremely ~table and may be easily readied for administration by coupling to the ~ubstance having binding affinity for the target tis~ue.
The degree of magnetization of the magnetic micro-particles, when magnetically polarized, will cause a ~ubstantial local perturbation to the steady magnetic field applied to the ~arget tis~ue, the detail~ of the perturbation depending on the magnetic material selected and the~particle ~ize thereof. Thi~ high degree of L~6~
magnetization exerts an extremely ~trong influence on nuclear relaxation time. The magnetic effect of this contra~t agent cau~e~ magnetic pha~e perturbation in nuclei up to about 20 micron~ or more removed from the contrast agent, permitting extremely small amount~ of the agent to be u3ed, e.g. on th,e order of one to ten magnetic micro-particles per cell, thus providing a NMR
contra~t agent oE exceptional sensitivity, enabling the detection of the distribution and transfer of neurotransmitter substances iand low level hormone receptor~. The u~e of bio-compatible coating~ on the magnetic particle~ renders them free of toxic or other undersirable side effects. The contra~t agent of the present invention also enable~ selective tissue targeting by rea~on of the coupling thereto of a substance having binding affinity for the target tissue. With regard to deactivation of the contra~t agent, it i3 believed that over time it will be taken up by macrophaqe~ and strored in the body.
The contrast agent of the pre~ent invention may be used to particular advantage in tumor imaging by the u~e of magnetic micro-particle~ comprising magnetic material coupled eO antibody which bind3 specifically to tumor-associated antigen. Other feature~ and advantages of the inYention will become apparent to those skilled in the art from the following detailed descripeion thereof.
DETAILED DESCRIPTION OF THE INVENTION
Various magnetic materials may be used in preparing the magnetic micro-particles employed in the present invention. As used herein, the term ~magnetic materials"
refers to those materials exhibiting ferromagnetism, and include3 materials having a high magnetic su~ceptibity - 6 ~
such that their internal magnetic field~ are on the order of about one thousand gauss. Ferromagnetic material3 useful in the pre~ent invention are characterized by having domains of magnetism which become aligned with an external magnetic field, thus producing a high internal magentic field. Suitable magnetic material includs iron, cobalt, nickel and manganese. Compounds or alloy~
of the~e elements which exhibit ferromagnetism, e.g.
magnetite (Fe304) or Mn-Cu alloy may also be used.
The size of the magnetic micro-particles will depend on the target organ system. In general, the average particle size will be greater than few hundred Angstrom units, but leqs than about one micron.
The substance having tissue-binding affinity that is selected for coupling to the magnetic micro-particles will be determined by the particular tissue whose image is desired. Examples of such substances include antibodies, preferably monoclonal antibodies, neurotransmitters, hormones, matabolite~, enzymes, toxins, and natural or ~ynthetic drugs. Analogues of these substances may also be employed, if desired. As used herein the term "analogue" refers to synthetic materials that elicit a physioloqical response comparable to that of the natural substance.
A~ previously noted, the sub~tance having tissue-binding affinity may be coupled to the magnetic micro-particles according to procedures well known in the art. This may be most conveniently accomplished by providing the magnetic micro-particles with a polymer coating having reactive functional 9rOUpB~ and attachinq the tissue-apecific ~ubstance to the polymer coating by chemical bonding to the functional groups of the polymer.
A polymer coating may be applied to the magnetic material by a redox polymerization proce3s wherein a metal oxide, e.g. magnetite serves as a source of reducing agent in the redox activation system. Such a process i3 describecl in U.S. Patent No. ~,157,323 t*e~ ~e-d~sc~s~rF-uf--~h~ ~e~r-a-t~ ~ i~-t-he-~r~t--~p~lic~ti~_by -Eefer~en~-aff-~h~h-se-t--f-~r-lh-he~e-~-i~ full. Polymer coating~ may also be applied to magnetic substrates according to the procedure described in ~.S. Patent No.
4,070,246. Polymer-coated nnagnetic micro-particles are commercially available from a number of sources.
Bio-compatible polymer~ are preferred for use in the present invention. The term "bio-compatible polymer~ i9 intended to qignify a polymer that doe~ not produce any significant toxic effect or other undesirable effect on the test subject to whom the magnetic micro-particles are administered. Bio-compatible polymers may be either synthetic or naturally occuring, representatiYe examples of such polymers being albumin and polystyrene. In addition to facilitating the coupling of the tissue-specific substance, the bio-compatible polymer coating serves to prevent adverse physiological effect~
caused by the magnetic material and to prevent deterioration of the magnetic material by chemicals present in the environment in which the magnetic micro-particles are u~ed.
The ti~sue-Apecific substance may be coupled to the polymer-coated magnetic material by methods familiar to those ~killed in art, ~uch as by covalent bonding, as noted above, or by ionic or hydrogen bonding. Suitable methods for thi~ purpose are disclosed in the aforementioned U.S. Patent No. 4,157,323.
The presently preferred mode of administration of the magnetic micro-particles is by intravenous injection, although other suitable technique~ for introducing the contrast agent into the area of NM~ imaging examination ~2~
may also be used, if desired.
The dosage at which the magnetic micro-particles i~
admini~tered will vary depending on the test subject and the nature of the ti~sue ~ought to be imaged. While it S i9 contemplated that the pre~ent invention will ultimately be used in NMR imaging of human ti~sue, ~uch use ha3 not yet been undertaken. However, the present invention ha3 considerable utility in NMR imaging of the organ systems of lower animals for differention of normal and pathologic tissue, characterization of pathologic tissue, characterization of physiologic or pathologic phenomena, and the like.
The pulse sequence used in obtaing the NMR image in accordance with the present invention should be one which has high sensitivity to spin-spin relaxation parameters.
Although the scientific principle underlying the present invention has not been thoroughly investigated, and is not completely understood, it i3 believed that the magr.etic micro-particle functions as a ~mall magnetic dipole which produces a magnetic field that causes perturbation of the nuclei of water molecules surrounding the magnetic micro-particles in the tissue under examination. The magnetic field will dissipate by the third power of the distance from the magnetic micro-particle. Thus, aq water molecule~ diffuse through the varying magnetic field cau~ed by the presence of the magnetic micro-particles, their magnetic pha~e is seriously perturbed, causing a ~ubstantial reduction in the apparent ~pin-spin relaxation time, and thereby enhancing contrast in the resultant NMR image.
The procedures for obtaining an image of body tis~ue using NMR are well known to those ~killed in the art.
Basic concepts of NMR imaging are set forth in Kaufman et al (eds.) Nuclear Magnetic Resonance Imaging In Medicine~
New York: Igaku-Shoin, 1981. A number of commercial supplier~ exist for NMR imaging apparatus~
Regarding specific applications, the present invention may be used for imaging tumors. Before carrying out this particular application, however, the primary tumor is removed and the tumor antigen is used for the production of monoclonoal antibodies specific the tumor associated antigen. Thereafter, polymer coated magnetic micro-particles are derivatized with the monoclonal antibody. The derivatized magnetic micro~particles are then administered to the te~t subject and after a time sufficient for the magnetic micro-particles to bind to the tumor a~sociated antigen, the NMR image is obtained. The present invention may also be used in obtaining images of the distribution and transfer of specific neurotran~mitter~ in nervous ti~sue, by coupling a neurotransmitter or a neurotransmitter analogue ~o magnetic micro-particles, which are then administered to the test subject and an NMR image of the nervous tissue i~ obtained. Another application of the present invention is in imaging the interaction between hormones and hormone-binding tissues. In this application the magnetic micro-particle comprises magnetic material coupled to a hormone or hormone analogue which binds specifically to receptors associated with the hormone-binding tissue. The image produced by these and other applications of the pre~ent ~nvention should provide valuable information for diagnosising many dieases.
While certain embodiments of the present invention have been described hereinabove, it i~ not intended to limit the invention to such embodiments, but various modifications and may be made therein and thereto without departing from the spirit and scope of the invention as set forth in the following claims.
Claims (9)
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. In a method for producing an image of animal tissue by nuclear magnetic resonance imaging, the improvement which comprise binding to the tissue whose image is desired a magnetic micro-particle comprising magnetic material coupled to a substance having binding affinity for said tissue, in an amount effective for causing a substantial reduction in the relaxation time of nearby nuclei, thereby to effect contrast enhancement in the resulting image.
2. A method according to claim 1, wherein the magnetic material is coupled to the substance having binding affinity for said tissue by coating the magnetic material with a bio-compatible polymer having reactive functional groups and reacting said functional groups with said substance to form chemical bonds therebetween.
3. A method according to claim 1, wherein the tissue is tumor tissue, and the magnetic micro-particle comprises magnetic material coupled to antibody which binds specifically to antigen associated with said tumor.
4. A method according to claim 3, wherein the antibody is monoclonal antibody.
5. A method according to claim 1, wherein the tissue is nervous tissue and the magnetic micro-particle comprises magnetic material coupled to a neurotransmitter or a neurotransmitter analogue which binds specifically to receptors associated with said nervous tissue.
6. A method according to claim 1 wherein the tissue is a hormone-binding tissue and the micro-particle comprises magnetic material coupled to a hormone or hormone analogue which binds specifically to receptors associated with said tissue.
7. A method for obtaining contrast enhancement in an image of animal tissue produced by nuclear magnetic resonance imaging, which comprises introducing to the area of the tissue whose image is desired magnetic micro-particles comprising ferromagnetic material, the amount of said magnetic micro-particles being effective for causing a substantial reduction in the relaxation time of nearly nuclei, and producing an image of said tissue by nuclear magnetic resonance imaging.
8. A method according to claim 7 wherein the magnetic micro-particles have an average particle size of 1 micron or less.
9. A method according to claim 7, wherein the magnetic micro-particles are introduced by injection.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US64003784A | 1984-08-10 | 1984-08-10 | |
| US640,037 | 1984-08-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1268208A true CA1268208A (en) | 1990-04-24 |
Family
ID=24566571
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000485587A Expired - Fee Related CA1268208A (en) | 1984-08-10 | 1985-06-27 | Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging |
Country Status (4)
| Country | Link |
|---|---|
| CA (1) | CA1268208A (en) |
| DE (1) | DE3590398T1 (en) |
| GB (1) | GB2177199A (en) |
| WO (1) | WO1986001112A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223242A (en) * | 1985-11-05 | 1993-06-29 | The General Hospital Corporation | Negatively charged specific affinity reagents |
| EP0268707A3 (en) * | 1985-11-05 | 1989-03-08 | The General Hospital Corporation | Negatively charged specific affinity reagents |
| US5055288A (en) * | 1987-06-26 | 1991-10-08 | Advanced Magnetics, Inc. | Vascular magnetic imaging method and agent comprising biodegradeable superparamagnetic metal oxides |
| US5314679A (en) * | 1986-07-03 | 1994-05-24 | Advanced Magnetics Inc. | Vascular magnetic resonance imaging agent comprising nanoparticles |
| FR2612400A1 (en) * | 1987-03-16 | 1988-09-23 | Centre Nat Rech Scient | Microcapsules containing a radioactive and/or paramagnetic label in chelate form, and their use in the field of medical imaging |
| DE3709851A1 (en) * | 1987-03-24 | 1988-10-06 | Silica Gel Gmbh Adsorptions Te | NMR DIAGNOSTIC LIQUID COMPOSITIONS |
| US5314681A (en) * | 1988-12-23 | 1994-05-24 | Nycomed Innovation Ab | Composition of positive and negative contrast agents for electron spin resonance enhanced magnetic resonance imaging |
| US5164297A (en) * | 1990-05-03 | 1992-11-17 | Advanced Magnetics Inc. | Solvent mediated relaxation assay system |
| ATE166233T1 (en) * | 1990-09-14 | 1998-06-15 | Syngenix Ltd | USE OF SUBSTANCES IN PARTICLE FORM |
| GB9020075D0 (en) * | 1990-09-14 | 1990-10-24 | Filler Aaron G | Contrast agents for magnetic resonance imaging of axonal transport |
| US5948384A (en) * | 1990-09-14 | 1999-09-07 | Syngenix Limited | Particulate agents |
| US6919067B2 (en) | 1991-09-13 | 2005-07-19 | Syngenix Limited | Compositions comprising a tissue glue and therapeutic agents |
| DE4309333A1 (en) * | 1993-03-17 | 1994-09-22 | Silica Gel Gmbh | Superparamagnetic particles, process for their production and use thereof |
| DE69628731T3 (en) * | 1995-11-01 | 2012-09-20 | Bracco Suisse S.A. | TARGETED MAGNETICALLY MARKED MOLECULAR MARKER SYSTEMS AS NMR IMAGING PRODUCTS |
| CA2242647A1 (en) | 1996-01-10 | 1997-07-17 | Amersham Health As | Contrast media |
| GB9600427D0 (en) * | 1996-01-10 | 1996-03-13 | Nycomed Imaging As | Contrast media |
| US8669236B2 (en) | 2005-05-12 | 2014-03-11 | The General Hospital Corporation | Biotinylated compositions |
| AU2013308519A1 (en) | 2012-08-31 | 2015-04-09 | The General Hospital Corporation | Biotin complexes for treatment and diagnosis of Alzheimer's disease |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3129906C3 (en) * | 1981-07-24 | 1996-12-19 | Schering Ag | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
| US4452773A (en) * | 1982-04-05 | 1984-06-05 | Canadian Patents And Development Limited | Magnetic iron-dextran microspheres |
| US4454106A (en) * | 1982-06-07 | 1984-06-12 | Gansow Otto A | Use of metal chelate conjugated monoclonal antibodies |
-
1985
- 1985-06-27 CA CA000485587A patent/CA1268208A/en not_active Expired - Fee Related
- 1985-08-06 DE DE19853590398 patent/DE3590398T1/en not_active Withdrawn
- 1985-08-06 GB GB08607629A patent/GB2177199A/en not_active Withdrawn
- 1985-08-06 WO PCT/US1985/001495 patent/WO1986001112A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| GB2177199A (en) | 1987-01-14 |
| WO1986001112A1 (en) | 1986-02-27 |
| GB8607629D0 (en) | 1986-04-30 |
| DE3590398T1 (en) | 1986-08-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1268208A (en) | Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging | |
| US4863715A (en) | Method of NMK imaging using a contrast agent comprising particles of a ferromagnetic material | |
| Renshaw et al. | Ferromagnetic contrast agents: a new approach | |
| US5069216A (en) | Silanized biodegradable super paramagnetic metal oxides as contrast agents for imaging the gastrointestinal tract | |
| US4827945A (en) | Biologically degradable superparamagnetic materials for use in clinical applications | |
| US4951675A (en) | Biodegradable superparamagnetic metal oxides as contrast agents for MR imaging | |
| Artemov et al. | MR molecular imaging of the Her‐2/neu receptor in breast cancer cells using targeted iron oxide nanoparticles | |
| AU652829B2 (en) | Melanin-based agents for image enhancement | |
| US4770183A (en) | Biologically degradable superparamagnetic particles for use as nuclear magnetic resonance imaging agents | |
| Renshaw et al. | Immunospecific NMR contrast agents | |
| US5219554A (en) | Hydrated biodegradable superparamagnetic metal oxides | |
| Groman et al. | Ultrasmall mixed ferrite colloids as multidimensional magnetic resonance imaging, cell labeling, and cell sorting agents | |
| Zhu et al. | Fluorescent magnetic Fe3O4/rare earth colloidal nanoparticles for dual‐modality imaging | |
| US5330742A (en) | Methods and compositions for magnetic resonance imaging | |
| Zhong et al. | A rheumatoid arthritis magnetic resonance imaging contrast agent based on folic acid conjugated PEG-b-PAA@ SPION | |
| Sung et al. | Dual-modal nanoprobes for imaging of mesenchymal stem cell transplant by MRI and fluorescence imaging | |
| JP5350257B2 (en) | Imaging of activated vascular endothelium using immunomagnetic MRI contrast agents | |
| Lahooti et al. | Preliminary studies of 68Ga-NODA-USPION-BBN as a dual-modality contrast agent for use in positron emission tomography/magnetic resonance imaging | |
| CA2201750A1 (en) | Chelate complex with high conspicuity for magnetic resonance imaging | |
| CHOI et al. | Necrotic areas in VX2 carcinoma of rabbits: correlation of magnetic resonance imaging and pathologic appearance | |
| CA2271735C (en) | Magnetic resonance blood pool agents | |
| Suto et al. | Dual contrast magnetic resonance imaging with combined use of positive and negative contrast agent in human hepatocellular carcinoma | |
| Amraee et al. | Ultrasmall iron oxide nanoparticles and gadolinium-based contrast agents in magnetic resonance imaging: a systematic review and meta-analysis | |
| WO1995009564A1 (en) | Compositions and methods for magnetic resonance imaging, x-ray imaging and radiopharmaceuticals | |
| Matsumura et al. | Proton relaxation caused by magnetic resonance imaging contrast agent, oral magnetic particles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |