WO1986001112A1 - Les microparticules comme agents de contraste dans la production d'images par resonance magnetique nucleaire - Google Patents
Les microparticules comme agents de contraste dans la production d'images par resonance magnetique nucleaire Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tissue
- magnetic
- micro
- magnetic material
- particles
- Prior art date
Links
- 230000005291 magnetic effect Effects 0.000 title claims abstract description 52
- 239000011859 microparticle Substances 0.000 title claims abstract description 35
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 title claims description 5
- 239000002872 contrast media Substances 0.000 title description 18
- 239000000126 substance Substances 0.000 claims abstract description 25
- 239000000696 magnetic material Substances 0.000 claims abstract description 21
- 230000027455 binding Effects 0.000 claims abstract description 15
- 241001465754 Metazoa Species 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 17
- 229920000642 polymer Polymers 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 239000005556 hormone Substances 0.000 claims description 9
- 229940088597 hormone Drugs 0.000 claims description 9
- 238000000576 coating method Methods 0.000 claims description 8
- 239000011248 coating agent Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 6
- 239000002858 neurotransmitter agent Substances 0.000 claims description 6
- 239000000427 antigen Substances 0.000 claims description 5
- 108091007433 antigens Proteins 0.000 claims description 5
- 102000036639 antigens Human genes 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 230000006872 improvement Effects 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 abstract description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 210000004789 organ system Anatomy 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 239000000193 iodinated contrast media Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000005307 ferromagnetism Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000006249 magnetic particle Substances 0.000 description 2
- 230000005415 magnetization Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000002601 radiography Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 229910000881 Cu alloy Inorganic materials 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003302 ferromagnetic material Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002075 inversion recovery Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000007620 mathematical function Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007717 redox polymerization reaction Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
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
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 ⁇ .
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- 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
La production d'images par RMN est améliorée à l'aide d'un agent d'intensification de contraste sous la forme de microparticules, composées d'un matériau magnétique, associées, à une substance possédant une affinité de liaison pour le tissu-cible.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08607629A GB2177199A (en) | 1984-08-10 | 1985-08-06 | Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging |
DE19853590398 DE3590398T1 (de) | 1984-08-10 | 1985-08-06 | Magnetische Mikroteilchen als Kontrastmittel für magnetische Kernresonanzabbildung |
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 |
---|---|
WO1986001112A1 true WO1986001112A1 (fr) | 1986-02-27 |
Family
ID=24566571
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1985/001495 WO1986001112A1 (fr) | 1984-08-10 | 1985-08-06 | Les microparticules comme agents de contraste dans la production d'images par resonance magnetique nucleaire |
Country Status (4)
Country | Link |
---|---|
CA (1) | CA1268208A (fr) |
DE (1) | DE3590398T1 (fr) |
GB (1) | GB2177199A (fr) |
WO (1) | WO1986001112A1 (fr) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2612400A1 (fr) * | 1987-03-16 | 1988-09-23 | Centre Nat Rech Scient | Microcapsules contenant un marqueur radioactif et/ou paramagnetique sous forme de chelate, et leur utilisation dans le domaine de l'imagerie medicale |
EP0268707A3 (fr) * | 1985-11-05 | 1989-03-08 | The General Hospital Corporation | Réactifs d'affinité spécifique portant une charge négative |
EP0284549A3 (en) * | 1987-03-24 | 1989-09-13 | Silica Gel Gesellschaft Mbh Adsorptions-Technik, 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 |
WO1991017428A1 (fr) * | 1990-05-03 | 1991-11-14 | Advanced Magnetics Inc. | Systeme d'analyse utilisant la liberation de protons par un solvant |
WO1992004916A3 (fr) * | 1990-09-14 | 1992-08-20 | St George S Enterprises Ltd | Agents sous forme de particules |
US5223242A (en) * | 1985-11-05 | 1993-06-29 | 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 |
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 |
WO1997016474A1 (fr) * | 1995-11-01 | 1997-05-09 | Bracco Research S.A. | Systemes de marqueur moleculaire cible, a etiquetage magnetique, pour imagerie a resonance magnetique nucleaire |
US5948384A (en) * | 1990-09-14 | 1999-09-07 | Syngenix Limited | Particulate agents |
US6123920A (en) * | 1996-01-10 | 2000-09-26 | Nycomed Imaging As | Superparamagnetic contrast media coated with starch and polyalkylene oxides |
EP0861667A3 (fr) * | 1990-09-14 | 2001-08-08 | Syngenix Limited | Agents particulaires |
US6423296B1 (en) | 1996-01-10 | 2002-07-23 | Amersham Health As | Constrast media |
US6919067B2 (en) | 1991-09-13 | 2005-07-19 | Syngenix Limited | Compositions comprising a tissue glue and therapeutic agents |
US8669236B2 (en) | 2005-05-12 | 2014-03-11 | The General Hospital Corporation | Biotinylated compositions |
US10532104B2 (en) | 2012-08-31 | 2020-01-14 | The General Hospital Corporation | Biotin complexes for treatment and diagnosis of Alzheimer'S disease |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4309333A1 (de) * | 1993-03-17 | 1994-09-22 | Silica Gel Gmbh | Superparamagnetische Teilchen, Verfahren zu ihrer Herstellung und Verwendung derselben |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU8633082A (en) * | 1981-07-24 | 1983-01-27 | Schering Aktiengesellschaft | Paramagnetic complex salts and their 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/fr not_active Expired
- 1985-08-06 DE DE19853590398 patent/DE3590398T1/de not_active Withdrawn
- 1985-08-06 WO PCT/US1985/001495 patent/WO1986001112A1/fr active Application Filing
- 1985-08-06 GB GB08607629A patent/GB2177199A/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU8633082A (en) * | 1981-07-24 | 1983-01-27 | Schering Aktiengesellschaft | Paramagnetic complex salts and their use in nmr- diagnostics |
EP0071564A1 (fr) * | 1981-07-24 | 1983-02-09 | Schering Aktiengesellschaft | Sels complexes paramagnétiques, leur préparation et leur utilisation en diagnostique avec RMN |
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 |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0268707A3 (fr) * | 1985-11-05 | 1989-03-08 | The General Hospital Corporation | Réactifs d'affinité spécifique portant une charge négative |
US5223242A (en) * | 1985-11-05 | 1993-06-29 | 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 (fr) * | 1987-03-16 | 1988-09-23 | Centre Nat Rech Scient | Microcapsules contenant un marqueur radioactif et/ou paramagnetique sous forme de chelate, et leur utilisation dans le domaine de l'imagerie medicale |
EP0284549A3 (en) * | 1987-03-24 | 1989-09-13 | Silica Gel Gesellschaft Mbh Adsorptions-Technik, 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 |
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 |
WO1991017428A1 (fr) * | 1990-05-03 | 1991-11-14 | Advanced Magnetics Inc. | Systeme d'analyse utilisant la liberation de protons par un solvant |
WO1992004916A3 (fr) * | 1990-09-14 | 1992-08-20 | St George S Enterprises Ltd | Agents sous forme de particules |
US5948384A (en) * | 1990-09-14 | 1999-09-07 | Syngenix Limited | Particulate agents |
EP0861667A3 (fr) * | 1990-09-14 | 2001-08-08 | Syngenix Limited | Agents particulaires |
US6562318B1 (en) | 1990-09-14 | 2003-05-13 | Syngenix Limited | Particular agents |
US6919067B2 (en) | 1991-09-13 | 2005-07-19 | Syngenix Limited | Compositions comprising a tissue glue and therapeutic agents |
WO1997016474A1 (fr) * | 1995-11-01 | 1997-05-09 | Bracco Research S.A. | Systemes de marqueur moleculaire cible, a etiquetage magnetique, pour imagerie a resonance magnetique nucleaire |
US5910300A (en) * | 1995-11-01 | 1999-06-08 | Bracco Research S.A. | Amphiphilic linkers for coupling administrable diagnostically or physiologically active agents and bioselective targeting compounds |
US6123920A (en) * | 1996-01-10 | 2000-09-26 | Nycomed Imaging As | Superparamagnetic contrast media coated with starch and polyalkylene oxides |
US6423296B1 (en) | 1996-01-10 | 2002-07-23 | Amersham Health As | Constrast media |
US8669236B2 (en) | 2005-05-12 | 2014-03-11 | The General Hospital Corporation | Biotinylated compositions |
US10532104B2 (en) | 2012-08-31 | 2020-01-14 | The General Hospital Corporation | Biotin complexes for treatment and diagnosis of Alzheimer'S disease |
Also Published As
Publication number | Publication date |
---|---|
CA1268208A (fr) | 1990-04-24 |
GB2177199A (en) | 1987-01-14 |
GB8607629D0 (en) | 1986-04-30 |
DE3590398T1 (de) | 1986-08-28 |
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