WO1986001112A1 - Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging - Google Patents

Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging Download PDF

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Publication number
WO1986001112A1
WO1986001112A1 PCT/US1985/001495 US8501495W WO8601112A1 WO 1986001112 A1 WO1986001112 A1 WO 1986001112A1 US 8501495 W US8501495 W US 8501495W WO 8601112 A1 WO8601112 A1 WO 8601112A1
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Prior art keywords
tissue
magnetic
micro
magnetic material
particles
Prior art date
Application number
PCT/US1985/001495
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French (fr)
Inventor
Truman Brown
Original Assignee
Fox Chase Cancer Center
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Fox Chase Cancer Center filed Critical Fox Chase Cancer Center
Priority to DE19853590398 priority Critical patent/DE3590398T1/en
Priority to GB08607629A priority patent/GB2177199A/en
Publication of WO1986001112A1 publication Critical patent/WO1986001112A1/en

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    • 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

Definitions

  • the present invention relates to an improvement in nuclear magnetic resonance (NMR) imaging and in particular to the use of tissue specific magnetic micro-particles as contrast enhancing agents in NMR imaging.
  • NMR nuclear magnetic resonance
  • NMR spectroscopy has been used for a number of years as an analytical technique for organic chemical structure determinations. This technique is based on the magnetic properties of nuclei containing odd numbers cf protons and neutrons. Nuclei possess an angular momentum whic , in conjunction with the charge thereof; produces a magnetic field; the axis of which is directed along the spin axis of each nucleus. The application of a magnetic field to the nuclei cause alteration of the natural spin directions ⁇ which become aligned either with or against the applied field. The nuclei also prece ⁇ or rotate about their axes at a characteristic frequency.
  • the rotational angle. may be changed by absorption of electro-magnetic energy through a pheno en known as resonance/ which involves impressing on the nuclei a second magnetic field of appropriate frequency to match that of their normal precession.
  • the spin-lattice relaxation time (T ⁇ > is the rate at which spin energy is converted into thermal energy and transferred to the aggregate of atoms or molecules under study.
  • the spin-spin relaxation time ( 2) 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 characteristic relaxation time depending on its chemical environment.
  • NMR technique has been further developed and refined to provide a potentially valuable diagnostic tool; enabling visualization of body tissue.
  • 'It is possible to distinguish between abnormal and normal tissue; e.g. a lesion and surrounding normal tissue; on the basis of differences in spin-lattice and/or spin-spin relaxation times.
  • Remarkably clear images are obtainable that can aid in the characterization of pathologic or physiologic processes within various organs; including the brain; kidneys; and heart.
  • a suitable radio frequency pulse sequence saturated-recovery; inversion-recovery or spin-echo
  • saturated-recovery inversion-recovery or spin-echo
  • the signal's exact' frequency; phase and strength are determined through a mathematical function known as a Fourier transform.
  • the signals are assigned shading intensity enabling a computer to convert the results into an image of the targeted organ system.
  • Contrast agents enhance the difference in signal observed between magnetically similar but histologically dissimilar tissue; giving images of superior contrast that provide maximum diagnostic information.
  • the mechanism of action of the specific magnetic micro-particles used as NMR contrast-enhancing agents in the present invention is to be distinguished from iodinated contrast media typically used in radiography. Magnetic micro-particles alter the magnetic environment in the target organ system; so as 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 neighboring nuclei.
  • iodinated contrast media used in radiography generally have a high electron density and effect contrast directly by absorption of x-rays. Such agents 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 contrast agents described herein are not observed directly on the image; since the magnetic effect produced on neighboring nuclei is the means of contrast enhancement. In order for a substance to be acceptable as an NMR contrast-enhancing agent a number of critica must be satisfied.
  • the contrast agent should be easily manufactured from relatively inexpensive starting materials; chemically stable and readily stored in a form suitable for administration.
  • the contrast agent should have a reasonably strong influence on proton relaxation times in relatively low concentrations; but be essentially free of toxic effects or other undesirable side effects in appropriate dosages.
  • the contrast agent should be tissue-specific; i.e. permit selective tissue targetting.
  • the contrast agent must remain stable in vivo and ultimately be deactivated or excreted.
  • an improved method for producing an image of animal tissue by nuclear magnetic resonance imaging which comprises binding to the tissue whose image is desired a magnetic micro-particle comprising magnetic material coupled to a substance having binding affinity for the animal tissue; in an amount effective for causing a substantial reduction in the relaxation time of nearby nuclei; thereby effecting contrast enhancement in the resulting image.
  • the magnetic material is conveniently coupled to the substance having binding affinity for the target tissue by coating the magnetic material with a bio-compatible polymer having reactive functional groups and forming chemical bonds between the functional groups and the substance having binding affinity for the target tissue.
  • the magnetic micro-particle used as a contrast- enhancing agent in the practice of the present invention fulfills all the criteria noted above.
  • the contrast agent is made from commercially available and relatively inexpensive magnetic materials; which are readily coupled to various tissue-specific binding substances by procedures well known to those skilled in art. Polymer coated magnetic particles are extremely stable and may be easily readied for administration by coupling to the substance having binding affinity for the target tissue.
  • the degree of magnetization of the magnetic micro-particles when magnetically polarized; will cause a substantial local perturbation to the steady magnetic field applied to the target tissue; the details of the perturbation depending on the magnetic material selected and the particle size thereof. This high degree of magnetization exerts an extremely strong influence on nuclear relaxation time.
  • the magnetic effect of this contrast agent causes magnetic phase perturbation in nuclei up to about 20 microns or more removed from the contrast agent; permitting extremely small amounts of the agent to be used; e.g. on the order of one to ten magnetic micro-particles per cell; thus providing a NMR contrast agent of exceptional sensitivity; enabling the detection of the distribution and transfer of neuro ransmitter substances and low level hormone receptors.
  • the use of bio-compatible coatings on the magnetic particles renders them free of toxic or other under ⁇ irable side effects.
  • the contrast agent of the present invention also enables selective tissue targeting by reason of the coupling thereto of a substance having binding affinity for the target tissue.
  • the contrast agent of the present invention may be used to particular advantage in tumor imaging by the use of magnetic micro-particles comprising magnetic material coupled to antibody which binds specifically to tumor-associated antigen.
  • Magnetic materials refers to those materials exhibiting ferromagnetism; and includes materials having a high magnetic ⁇ usceptibity such that their internal magnetic fields are on the order of about one thousand gauss.
  • Ferromagnetic materials useful in the present 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 materials include iron; cobalt / nickel and manganese. Compounds or alloys of these elements which exhibit ferromagnetism/ e.g. magnetite (F ⁇ ⁇ O. ⁇ ) 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 less 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/ metabolites, enzymes, toxins; and natural or synthetic drugs. Analogues of these substances may also be employed; if desired.
  • analogue refers to synthetic materials that elicit a physiological response comparable to that of the natural substance.
  • the substance having tissue-binding affinity may be coupled to the magnetic micro-particles according to procedures well known in the art.
  • a polymer coating may be applied to the magnetic material by a redox polymerization process wherein a metal oxide, . objection. .nagnecice serves as d source of reducing agent in the redox activation system.
  • a metal oxide . adjective. .nagnecice serves as d source of reducing agent in the redox activation system.
  • Polymer coatings may also be applied to magnetic substrates according to the procedure described in U.S. Patent No. 4/070,246.
  • Bio-compatible polymers are preferred for use in the present invention.
  • the term "bio-compatible polymer” is intended to signify a polymer that does 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
  • the bio-compatible polymer coating serves to prevent adverse physiological effects 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 used.
  • the tissue-specific substance may be coupled to the polymer-coated magnetic material by methods familiar to those skilled in art; such as by covalent bonding, as noted above, or by ionic or hydrogen bonding. Suitable methods for this 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 techniques for introducing the contrast agent into the area of NMR imaging examination may also be used; if desired.
  • the dosage at which the magnetic micro-particles is administered will vary depending on the test subject and the nature of the tissue sought to be imaged. While it is contemplated that the present invention will ultimately be used in NMR imaging of human tissue; such use has not yet been undertaken. However; the present invention has 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.
  • the scientific principle underlying the present invention has not been thoroughly investigated; and is not completely understood; it is believed that the magnetic micro-particle functions as a small 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.
  • the present invention may be used for imaging tumors.
  • the primary tumor is removed and the tumor antigen is used for the production of monoclonoal antibodies specific the tumor associated antigen.
  • polymer coated magnetic micro-particles are derivatized with the monoclonal antibody.
  • the derivatized magnetic micro-particles are then administered to the test subject and after a time sufficient for the magnetic micro-particles to bind to the tumor associated antigen; the NMR image is obtained.
  • the present invention may also be used in obtaining images of the distribution and transfer of specific neurotransmitters in nervous tissue; by coupling a neurotransmitter or a neurotransmitter analogue to magnetic micro-particles; which are then administered to the test subject and an NMR image of the nervous tissue is obtained.
  • Another application of the present .invention is in imaging the interaction between hormones and hormone-binding tissues.
  • 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 present invention should provide valuable information for diagnosi ⁇ ing many diease ⁇ .

Abstract

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

- 1 -
MAGNETIC MICRO-PARTICLES AS CONTRAST AGENTS IN NUCLEAR MAGNETIC RESONANCE IMAGING
BACKGROUND OF THE INVENTION
The present invention relates to an improvement in nuclear magnetic resonance (NMR) imaging and in particular to the use of tissue specific magnetic micro-particles as contrast enhancing agents in NMR imaging.
NMR spectroscopy has been used for a number of years as an analytical technique for organic chemical structure determinations. This technique is based on the magnetic properties of nuclei containing odd numbers cf protons and neutrons. Nuclei possess an angular momentum whic , in conjunction with the charge thereof; produces a magnetic field; the axis of which is directed along the spin axis of each nucleus. The application of a magnetic field to the nuclei cause alteration of the natural spin directions^ which become aligned either with or against the applied field. The nuclei also preceββ or rotate about their axes at a characteristic frequency.
The rotational angle.may be changed by absorption of electro-magnetic energy through a pheno en known as resonance/ which involves impressing on the nuclei a second magnetic field of appropriate frequency to match that of their normal precession. When the second magneeic field is interrupted or terminated; the nuclei return to their initial precession state; generating radio signals having a detectable decay rate or relaxation time. The spin-lattice relaxation time (Tι> is the rate at which spin energy is converted into thermal energy and transferred to the aggregate of atoms or molecules under study. The spin-spin relaxation time ( 2) 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 characteristic relaxation time depending on its chemical environment.
More recently; NMR technique has been further developed and refined to provide a potentially valuable diagnostic tool; enabling visualization of body tissue.
'It is possible to distinguish between abnormal and normal tissue; e.g. a lesion and surrounding normal tissue; on the basis of differences in spin-lattice and/or spin-spin relaxation times. Remarkably clear images are obtainable that can aid in the characterization of pathologic or physiologic processes 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 assigned shading intensity enabling a computer to convert the results into an image of the targeted organ system.
There have been numerous reports over the last several years 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 histologically dissimilar tissue; giving images of superior contrast that provide maximum diagnostic information. The mechanism of action of the specific magnetic micro-particles used as NMR contrast-enhancing agents in the present invention is to be distinguished from iodinated contrast media typically used in radiography. Magnetic micro-particles alter the magnetic environment in the target organ system; so as 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 neighboring nuclei. On the other hand; iodinated contrast media used in radiography generally have a high electron density and effect contrast directly by absorption of x-rays. Such agents 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 contrast agents described herein are not observed directly on the image; since the magnetic effect produced on neighboring nuclei is the means of contrast enhancement. In order for a substance to be acceptable as an NMR contrast-enhancing agent a number of critica must be satisfied. The contrast agent should be easily manufactured from relatively inexpensive starting materials; chemically stable and readily stored in a form suitable for administration. More importantly; the contrast agent should have a reasonably strong influence on proton relaxation times in relatively low concentrations; but be essentially free of toxic effects or other undesirable side effects in appropriate dosages. In addition; the contrast agent should be tissue-specific; i.e. permit selective tissue targetting. Furthermore; the contrast agent must remain stable in vivo and ultimately be deactivated or excreted. SUMMARY OF THE INVENTION
In accordance with the present invention there is provided an improved method for producing an image of animal tissue by nuclear magnetic resonance imaging; which comprises binding to the tissue whose image is desired a magnetic micro-particle comprising magnetic material coupled to a substance having binding affinity for the animal tissue; in an amount effective for causing a substantial reduction in the relaxation time of nearby nuclei; thereby effecting contrast enhancement in the resulting image. The magnetic material is conveniently coupled to the substance having binding affinity for the target tissue by coating the magnetic material with a bio-compatible polymer having reactive functional groups and forming chemical bonds between the functional groups and the substance having binding affinity for the target tissue.
The magnetic micro-particle used as a contrast- enhancing agent in the practice of the present invention fulfills all the criteria noted above. The contrast agent is made from commercially available and relatively inexpensive magnetic materials; which are readily coupled to various tissue-specific binding substances by procedures well known to those skilled in art. Polymer coated magnetic particles are extremely stable and may be easily readied for administration by coupling to the substance having binding affinity for the target tissue. The degree of magnetization of the magnetic micro-particles; when magnetically polarized; will cause a substantial local perturbation to the steady magnetic field applied to the target tissue; the details of the perturbation depending on the magnetic material selected and the particle size thereof. This high degree of magnetization exerts an extremely strong influence on nuclear relaxation time. The magnetic effect of this contrast agent causes magnetic phase perturbation in nuclei up to about 20 microns or more removed from the contrast agent; permitting extremely small amounts of the agent to be used; e.g. on the order of one to ten magnetic micro-particles per cell; thus providing a NMR contrast agent of exceptional sensitivity; enabling the detection of the distribution and transfer of neuro ransmitter substances and low level hormone receptors. The use of bio-compatible coatings on the magnetic particles renders them free of toxic or other underβirable side effects. The contrast agent of the present invention also enables selective tissue targeting by reason of the coupling thereto of a substance having binding affinity for the target tissue. With regard to deactivation of the contrast agent; it is believed that over time it will be taken up by macrophages and strored in the body. The contrast agent of the present invention may be used to particular advantage in tumor imaging by the use of magnetic micro-particles comprising magnetic material coupled to antibody which binds specifically to tumor-associated antigen. Other features and advantages of the invention will become apparent to those skilled in the art from the following detailed description 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 includes materials having a high magnetic βusceptibity such that their internal magnetic fields are on the order of about one thousand gauss. Ferromagnetic materials useful in the present 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 materials include iron; cobalt/ nickel and manganese. Compounds or alloys of these elements which exhibit ferromagnetism/ e.g. magnetite (FββO.}) 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 less 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/ metabolites, enzymes, toxins; and natural or synthetic drugs. Analogues of these substances may also be employed; if desired. As used herein the term "analogue" refers to synthetic materials that elicit a physiological response comparable to that of the natural substance. As previously noted, the substance 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 groups; and attaching the tissue-specific substance 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 process wherein a metal oxide, .„. .nagnecice serves as d source of reducing agent in the redox activation system. Such a process is described in U.S. Patent No. 4,157/323 the entire disclosure of which is incorporated in the present application by reference as though set forth herein in full. Polymer coatings may also be applied to magnetic substrates according to the procedure described in U.S. Patent No. 4/070,246. Polymer-coated magnetic micro-particles are commercially available from a number of sources. Bio-compatible polymers are preferred for use in the present invention. The term "bio-compatible polymer" is intended to signify a polymer that does 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; representative 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 effects 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 used. The tissue-specific substance may be coupled to the polymer-coated magnetic material by methods familiar to those skilled in art; such as by covalent bonding, as noted above, or by ionic or hydrogen bonding. Suitable methods for this 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 techniques for introducing the contrast agent into the area of NMR imaging examination may also be used; if desired.
The dosage at which the magnetic micro-particles is administered will vary depending on the test subject and the nature of the tissue sought to be imaged. While it is contemplated that the present invention will ultimately be used in NMR imaging of human tissue; such use has not yet been undertaken. However; the present invention has 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 is believed that the magnetic micro-particle functions as a small 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; as water molecules diffuse through the varying magnetic field caused by the presence of the magnetic micro-particles/ their magnetic phase is seriously perturbed; causing a substantial reduction in the apparent spin-spin relaxation time; and thereby enhancing contrast in the resultant NMR image.
The procedures for obtaining an image of body tissue using NMR are well known to those skilled in the art. Basic concepts of NMR imaging are set forth in Kaufman et al (edβ.) Nuclear Magnetic Resonance Imaging In Medicine. New York: Igaku-Shoin; 1981. A number of commercial suppliers 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 test subject and after a time sufficient for the magnetic micro-particles to bind to the tumor associated antigen; the NMR image is obtained. The present invention may also be used in obtaining images of the distribution and transfer of specific neurotransmitters in nervous tissue; by coupling a neurotransmitter or a neurotransmitter analogue to magnetic micro-particles; which are then administered to the test subject and an NMR image of the nervous tissue is 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 present invention should provide valuable information for diagnosiβing many dieaseβ.
While certain embodiments of the present invention have been described hereinabovβ/ it ia 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

What is claimed is:
1. In a method for producing an image of animal tissue by nuclear magnetic resonance imaging; the improvement which comprises 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.
PCT/US1985/001495 1984-08-10 1985-08-06 Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging WO1986001112A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE19853590398 DE3590398T1 (en) 1984-08-10 1985-08-06 Magnetic microparticles as a contrast medium for magnetic resonance imaging
GB08607629A GB2177199A (en) 1984-08-10 1985-08-06 Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging

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US64003784A 1984-08-10 1984-08-10
US640,037 1984-08-10

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EP0284549A2 (en) * 1987-03-24 1988-09-28 Silica Gel Ges.mbH Absorptionstechnik, Apparatebau Magnetic fluid compositions
US5055288A (en) * 1987-06-26 1991-10-08 Advanced Magnetics, Inc. Vascular magnetic imaging method and agent comprising biodegradeable superparamagnetic metal oxides
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Cited By (23)

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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
EP0268707A2 (en) * 1985-11-05 1988-06-01 The General Hospital Corporation Negatively charged specific affinity reagents
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
EP0284549A2 (en) * 1987-03-24 1988-09-28 Silica Gel Ges.mbH Absorptionstechnik, Apparatebau Magnetic fluid compositions
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GB2177199A (en) 1987-01-14
DE3590398T1 (en) 1986-08-28
GB8607629D0 (en) 1986-04-30
CA1268208A (en) 1990-04-24

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