DE4427821A1 - Stabilised super-paramagnetic aggregate particles - Google Patents
Stabilised super-paramagnetic aggregate particlesInfo
- Publication number
- DE4427821A1 DE4427821A1 DE4427821A DE4427821A DE4427821A1 DE 4427821 A1 DE4427821 A1 DE 4427821A1 DE 4427821 A DE4427821 A DE 4427821A DE 4427821 A DE4427821 A DE 4427821A DE 4427821 A1 DE4427821 A1 DE 4427821A1
- Authority
- DE
- Germany
- Prior art keywords
- substances
- particles
- superparamagnetic
- pharmacologically active
- group
- 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.)
- Withdrawn
Links
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- 239000010452 phosphate Substances 0.000 claims abstract description 9
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229920000388 Polyphosphate Polymers 0.000 claims abstract description 8
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- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims abstract description 8
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- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims abstract description 7
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- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 claims description 6
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Abstract
Description
Die Erfindung betrifft superparamagnetische Teilchen, die aus
Aggregaten von superparamagnetischen Eindomänenteilchen aus
Eisenoxiden, Eisenmischoxiden oder Eisen bestehen und die auf
ihrer Oberfläche organische Substanzen gebunden haben, die ge
gebenfalls weitere Bindungsstellen zur Kopplung von gewebespe
zifischen Bindungssubstanzen, diagnostischen oder pharmakolo
gisch wirksamen Substanzen besitzen,
nach Patent (Patentanmeldung P 43 09 333.7).The invention relates to superparamagnetic particles which consist of aggregates of superparamagnetic single-domain particles made of iron oxides, mixed iron oxides or iron and which have organic substances bound on their surface, which may have further binding sites for coupling tissue-specific binding substances, diagnostic or pharmacologically active substances,
according to patent (patent application P 43 09 333.7).
Im Hauptpatent werden superparamagnetische Teilchen beschrie ben, die aus stabilen abbaubaren Aggregaten mit einer Teilchen größe im Bereich zwischen 10 und 1000 Nanometer bestehen mit definiertem Verhalten im Magnetfeld, wobei die Aggregate aus mehreren kleinen superparamagnetischen Eindomänenteilchen aus Eisenoxid-, Eisenmischoxid- oder Eisen mit einer Teilchengröße im Bereich zwischen 3 und 20 Nanometer bestehen, die auf ihrer Oberfläche organische Substanzen der Gruppe der phosphat-, diphosphat -, polyphosphat-, thiophosphat-, phosphonat- oder thiophosphonatgruppenhaltige Polyalkylenglykole, phosphatgrup penhaltige Nucleotide, deren Oligomere oder deren Polymere so wie phosphatgruppenhaltige Kohlehydrate chemisch gebunden tra gen, die weitere Bindungsstellen haben können.The main patent describes superparamagnetic particles ben that consist of stable degradable aggregates with one particle with sizes in the range between 10 and 1000 nanometers defined behavior in the magnetic field, whereby the aggregates from several small superparamagnetic single domain particles Iron oxide, mixed iron oxide or iron with a particle size exist in the range between 3 and 20 nanometers on their Surface organic substances of the group of phosphate, diphosphate, polyphosphate, thiophosphate, phosphonate or polyalkylene glycols containing thiophosphonate groups, phosphate group nucleotides containing pen, their oligomers or their polymers so like carbohydrates containing phosphate groups chemically bound tra gene, which may have further binding sites.
Der Erfindung liegt die Aufgabe zugrunde, den Bereich der Sub stanzen, die an der Oberfläche der Eindomänenteilchen gebunden sein können, zu erweitern, wobei diese Verbindungsgruppen sta bil und leicht herstellbar sein sollen.The invention has for its object the area of the sub punch that bound to the surface of the single domain particles can be expanded, these connecting groups sta bil and easy to manufacture.
Erfindungsgemäß erfolgt die Stabilisierung der Magnetteilchen durch eine Bindung vonAccording to the invention, the magnetic particles are stabilized through a bond of
- (i) mono- und/oder polyhydroxylgruppenhaltige aromatische Sub stanzen, ausgewählt unter Benzenoiden, Cumarinen, Lignanen, Terphenylen, Flavonoiden, Tanninen, Xanthonen, Benzophenonen, Naphthalenen, Naphthochinonen, Anthrachinonen, Anthracyclinen, polycyclische kondensierte aromatische Verbindungen und deren phosphat-, diphosphat-, polyphosphat-, thiophosphat-, phos phonat-, thiophosphonat-, carboxylat-, sulfat-, mercapto- oder silantriolgruppenhaltigen Derivaten,(i) Mono- and / or polyhydroxyl-containing aromatic sub punching, selected from benzenoids, coumarins, lignans, Terphenyls, flavonoids, tannins, xanthones, benzophenones, Naphthalenes, naphthoquinones, anthraquinones, anthracyclines, polycyclic condensed aromatic compounds and their phosphate, diphosphate, polyphosphate, thiophosphate, phos phonate, thiophosphonate, carboxylate, sulfate, mercapto or derivatives containing silanetriol groups,
- (ii) aminosäurenhaltige Substanzen, ausgewählt unter schwefel haltigen Aminosäuren, Oligopeptiden, Polypeptiden, Proteinen, Proteiden sowie deren Denaturierungsprodukten, und/oder(ii) substances containing amino acids selected from sulfur containing amino acids, oligopeptides, polypeptides, proteins, Proteins and their denaturing products, and / or
- (iii) den silikatgruppenhaltigen Substanzen der Orthokiesel säure und deren Kondensationsprodukten mit zwei und mehrwerti gen anorganischen Ionen und/oder organischen Säuren und Basen, ausgewählt unter phosphat-, diphosphat-, polyphosphat-, thio phosphat-, phosphonat- thiophosphonat-, sulfat-, sulfonat-, carboxylat-, mercapto-, silantriol-, aminosäuregruppenhaltigen organischen Substanzen auf der Oberfläche der superparamagneti sche Teilchen.(iii) the silicate group-containing substances of the orthosilica acid and its condensation products with two and more against inorganic ions and / or organic acids and bases, selected from phosphate, diphosphate, polyphosphate, thio phosphate, phosphonate, thiophosphonate, sulfate, sulfonate, carboxylate, mercapto, silanetriol, amino acid groups organic substances on the surface of the superparamagneti particles.
Die Stabilisatorsubstanz muß so beschaffen sein, daß sie mit Wasser mischbar ist und den Magnetteilchenabstand so groß hält, daß die kinetische Energie der Magnetteilchen größer als die magnetische Wechselwirkungsenergie ist.The stabilizer substance must be such that it with Water is miscible and keeps the magnetic particle spacing so large that the kinetic energy of the magnetic particles is larger than that is magnetic interaction energy.
Beispielhafte Stabilisatorsubstanzen für mono- und/oder polyhydroxylgruppenhaltige aromatische Substanzen sind Caffee säure, Gallussäure, Hexahydroxydiphensäure, Ellagsäure, Chebul säure, und deren Derivate und Kondensationsprodukte mit Kohlen hydraten und Phenolkarbonsäuren, Aesculin, Rutin, Aescin, Troxerutin, Hesperidin, Aloin, Kaempferol, Quercetin, Gallotannine, Ellagitannine, Ruberythrinsäure, Carminsäure, natürliche und synthetische Farbstoffe wie Anthrachinon- oder Phthalocyaninfarbstoffe, Daunorubicin, Ansamycin sowie deren phosphat-, diphosphat-, polyphosphat-, thiophosphat-, phos phonat-, thiophosphonat-, carboxylat-, sulfat-, mercapto- oder silantriolgruppenhaltigen Derivaten.Exemplary stabilizer substances for mono- and / or aromatic substances containing polyhydroxyl groups are coffee acid, gallic acid, hexahydroxydiphenic acid, ellagic acid, chebul acid, and their derivatives and condensation products with coal hydrates and phenolic carboxylic acids, aesculin, rutin, aescin, Troxerutin, hesperidin, aloin, kaempferol, quercetin, Gallotannins, Ellagitannins, Ruberythrinsäure, Carminsäure, natural and synthetic dyes such as anthraquinone or Phthalocyanine dyes, daunorubicin, ansamycin and their phosphate, diphosphate, polyphosphate, thiophosphate, phos phonate, thiophosphonate, carboxylate, sulfate, mercapto or Derivatives containing silanetriol groups.
Beispielhafte Stabilisatorsubstanzen für aminosäurenhaltige Substanzen sind Cystein, Methionin, Protamine, Glutathion, Gluteline, Albumine, Globuline, Gelatine, Casein-Hydrolysate.Exemplary stabilizer substances for those containing amino acids Substances are cysteine, methionine, protamine, glutathione, Gluteline, albumins, globulins, gelatin, casein hydrolyzates.
Beispielhafte Stabilisatorsubstanzen für silikatgruppenhaltige Substanzen der Orthokieselsäure und deren Kondensationsprodukte mit zwei und mehrwertigen anorganischen Ionen sind aluminium-, eisen-, wismuthaltige Kondensationsprodukte. Exemplary stabilizer substances for silicate groups Substances of orthosilicic acid and their condensation products with two and multivalent inorganic ions are aluminum, Condensation products containing iron and bismuth.
Beispielhafte Stabilisatorsubstanzen für silikatgruppenhaltige Substanzen der Orthokieselsäure und deren Kondensationsprodukte mit organischen Säuren und Basen sind Kondensationsprodukte mit Phytinsäure, Gerbsäure, ω-Methoxy-polyethylenglykol-tri methoxysilan (MG des PEG ca. 750), Alginsäure oder Kondensa tionsprodukte mit Albuminen.Exemplary stabilizer substances for silicate groups Substances of orthosilicic acid and their condensation products with organic acids and bases are condensation products with Phytic acid, tannic acid, ω-methoxy-polyethylene glycol-tri methoxysilane (MW of PEG approx. 750), alginic acid or condensate tion products with albumins.
Die Stabilisatorsubstanzen sind nach dem Stand der Technik her stellbar und können käuflich erworben werden.The stabilizer substances are based on the prior art adjustable and can be purchased.
Erfindungsgemäß können an die Stabilisatormoleküle, die mit ihren hydroxylgruppenhaltigen aromatischen Gruppen, amino säurenhaltige Substanzen und silikatgruppenhaltigen Substanzen der Orthokieselsäure und deren Kondensationsprodukten mit orga nischen Säuren und Basen, an der superparamagnetischen Teil chenoberfläche gebunden sind, gewebespezifische Bindungssub stanzen, pharmakologisch wirksame Substanzen, pharmakologisch wirksame Zellen, pharmakologisch wirksame Komplexbildner, zell fusionvermittelnde Substanzen, Pyrophosphorsäure, Pyrophosphor säureester, Polyphosphorsäureester und/oder deren Salze gebun den werden.According to the invention, the stabilizer molecules which have their hydroxyl-containing aromatic groups, amino acidic substances and silicate group-containing substances of orthosilicic acid and its condensation products with orga African acids and bases, on the superparamagnetic part surface, tissue-specific binding sub punching, pharmacologically active substances, pharmacologically effective cells, pharmacologically active complexing agents, cell fusion-mediating substances, pyrophosphoric acid, pyrophosphorus acid esters, polyphosphoric acid esters and / or their salts that will.
Die erfindungsgemäßen, mit hydroxylgruppenhaltigen aromatischen Stabilisatorsubstanzen stabilisierten superparamagnetischen Teilchen adsorbieren relativ fest aminosäurehaltige und aromatische Verbindungen, so daß für einige Anwendungsfälle eine reine adsorptive Bindung von gewebespezifische Bindungs substanzen, pharmakologisch wirksame Substanzen und pharmako logisch wirksame Zellen ausreichend ist, um sie für ein magne tischen drug targeting einsetzen zu können.The inventive, with aromatic hydroxyl groups Stabilizer substances stabilized superparamagnetic Particles adsorb relatively strong amino acid and aromatic compounds, so for some applications a pure adsorptive binding of tissue-specific binding substances, pharmacologically active substances and pharmaco Logically effective cells is sufficient to make them magne table drug targeting.
Die erfindungsgemäßen, mit aminosäuregruppenhaltigen Stabili satorsubstanzen stabilisierten superparamagnetischen Teilchen sind für viele Kopplungsreaktionen verwendbar, bei denen die Reaktivität der Aminosäuregruppen für eine chemische Bindung von gewebespezifische Bindungssubstanzen, pharmakologisch wirk same Substanzen und pharmakologisch wirksame Zellen anwendbar ist.The stabilizers according to the invention containing amino acid groups sator substances stabilized superparamagnetic particles can be used for many coupling reactions in which the Reactivity of the amino acid groups for chemical bonding of tissue-specific binding substances, pharmacologically active same substances and pharmacologically active cells applicable is.
Die erfindungsgemäßen, mit silikatgruppenhaltigen Substanzen der Orthokieselsäure und deren Kondensationsprodukten mit orga nischen Säuren und Basen, stabilisierten superparamagnetischen Teilchen sind für adsorptive Bindungen und für viele Kopplungs reaktionen verwendbar, bei denen die Reaktivität der funktio nellen Gruppen der organischen Säuren und Basen für eine chemi sche Bindung von gewebespezifische Bindungssubstanzen, pharma kologisch wirksame Substanzen und pharmakologisch wirksame Zel len anwendbar ist.The substances according to the invention containing silicate groups of orthosilicic acid and its condensation products with orga acids and bases, stabilized superparamagnetic Particles are for adsorptive bonds and for many couplings usable reactions in which the reactivity of the functio nelle groups of organic acids and bases for a chemi binding of tissue-specific binding substances, pharma ecologically active substances and pharmacologically active cells len is applicable.
Gewebespezifischen Bindungssubstanze sind z. B. Antigene, Anti körper, Haptene, Protein A, Protein G, Endotoxinbindende Pro teine, Lectine, Selectine. Tissue-specific binding substances are e.g. B. antigens, anti body, haptens, protein A, protein G, endotoxin binding pro teine, lectine, selectine.
Pharmakologisch wirksamen Substanzen sind z. B. Antitumorpro teine, Enzyme, Antitumorenzyme, Antibiotika, Pflanzenalkaloide, Alkylierungsreagenzien, Antimetaboliten, Hormone und Hormon antagonisten, Interleukine, Interferone, Wachstumsfaktoren, Tumornekrosefaktoren, Endotoxine, Lymphotoxine, Urokinase, Streptokinase, Plasminogen-Streptokinase-Aktivator-Komplex, Gewebe-Plasminogen-Aktivatoren, Desmodus-Plasminogen-Aktiva toren, Makrophagen-Aktivierungskörper, Antisera, Proteasen inhibitoren, radioakiven Phosphor 32P enthaltene Stabilisa torsubstanzen oder Tenside.Pharmacologically active substances are e.g. B. Antitumorpro teine, enzymes, antitumor enzymes, antibiotics, plant alkaloids, Alkylating reagents, antimetabolites, hormones and hormone antagonists, interleukins, interferons, growth factors, Tumor necrosis factors, endotoxins, lymphotoxins, urokinase, Streptokinase, plasminogen-streptokinase activator complex, Tissue plasminogen activators, desodus plasminogen assets gates, macrophage activation bodies, antisera, proteases inhibitors, radioactive phosphorus 32P contained Stabilisa door substances or surfactants.
Pharmakologisch wirksame Zellen sind z. B. Organellen, Viren, Mikroben, Algen, Pilzen, insbesondere Erythrozyten, Thrombo zyten, Granulozyten, Monozyten, Lymphozyten, Langerhans′sche Inseln.Pharmacologically active cells are e.g. B. organelles, viruses, Microbes, algae, fungi, especially erythrocytes, thrombo cysts, granulocytes, monocytes, lymphocytes, Langerhans'sche Islands.
Pharmakologisch wirksame Komplexbildner sind z. B. Polycarbon säuren, Aminocarboxylsäuren, Porphyrinen, Katecholamine.Pharmacologically active complexing agents are e.g. B. Polycarbonate acids, aminocarboxylic acids, porphyrins, catecholamines.
Zellfusionvermittelnde Substanzen sind z. B. Polyethylenglykole, Alkyl-aryl-polyethylenglykole.Cell fusion mediating substances are e.g. B. polyethylene glycols, Alkyl aryl polyethylene glycols.
Pyrophosphorsäure, Pyrophosphorsäureester und deren Salze sind z. B. mono-(ω-Methoxy-polyethylenglykol)-pyrophosphat (Molekulargewicht ca. 1100), Polyphosphorsäureester und deren Salze sind z. B. Natrium mono- (ω-Methoxy-polyethylenglykol)- triphosphat (Molekulargewicht ca. 600). Pyrophosphoric acid, pyrophosphoric acid esters and their salts e.g. B. mono- (ω-methoxy polyethylene glycol) pyrophosphate (Molecular weight approx. 1100), polyphosphoric acid esters and their Salts are e.g. B. Sodium mono- (ω-methoxy polyethylene glycol) - triphosphate (molecular weight approx. 600).
Die Toxizität solcher pharmakologisch wirksamen Substanzen kann dabei relativ hoch sein, da die Magnetteilchen sich aufgrund ihrer gewebespezifischen Wechselwirkung bevorzugt an den ent sprechenden Bindungsorten anreichert oder durch magnetisches drug targeting zum Wirkungsort transportiert und angereichert werden. Die Dosis der pharmakologisch wirksamen Substanzen kann gering gehalten werdend da sich die Substanz am Wirkungsort konzentriert und der übrige Körper nur gering belastet wird.The toxicity of such pharmacologically active substances can be relatively high because the magnetic particles are due to each other their tissue-specific interaction preferentially at the ent speaking binding sites or enriched by magnetic drug targeting transported to the site of action and enriched will. The dose of pharmacologically active substances can being kept low since the substance is at the site of action concentrated and the rest of the body is only slightly stressed.
Die Kopplung pharmakologisch wirksamer Substanzen an die super paramagnetischen Teilchen hat weiterhin den Vorteil, daß über die Relaxationszeitverkürzung der resonanzfähigen Wasserstoff atome im Körper der Therapiefortschritt mit der Kernspin- Diagnostik beobachtet werden kann.The coupling of pharmacologically active substances to the super paramagnetic particles also has the advantage that over the relaxation time reduction of the resonant hydrogen atoms in the body the therapy progress with the nuclear spin Diagnostics can be observed.
Die Herstellung der superparamagnetischen Teilchen erfolgt durch eine gezielte Agglomeration von superparamagnetischen Eindomänenteilchen. Dabei werden die superparamagnetischen Eindomänenteilchen in Wasser verrührt und bei einem pH-Wert von 3 bis 7 durch Erhitzen auf 80 bis 120°C, bei Temperaturen über 100°C im Autoklaven, zur Aggregation gebracht.The superparamagnetic particles are produced through a targeted agglomeration of superparamagnetic Single domain particles. The superparamagnetic One domain particle stirred in water and at a pH from 3 to 7 by heating to 80 to 120 ° C, at temperatures over 100 ° C in an autoclave, brought to aggregation.
Nach dem Abkühlen der Dispersion werden die Teilchen so lange gewaschen, bis die elektrische Leitfähigkeit des Filtrates < 10 µS/cm beträgt. Die so hergestellten superparamagnetischen Teilchen bilden sofort einen schnell sedimentierenden Nieder schlag, der sich auch durch starkes Rühren oder durch Ultra schallbehandlung nicht in eine stabile Dispersion überführen läßt. After the dispersion has cooled, the particles become so long washed until the electrical conductivity of the filtrate Is <10 µS / cm. The superparamagnetic manufactured in this way Particles immediately form a sediment that settles quickly blow, which is also due to strong stirring or ultra do not convert sound treatment into a stable dispersion leaves.
Erst die chemische Bindung von silantriol- und/oder mercapto gruppenhaltigen Stabilisatorsubstanzen auf der Oberfläche der superparamagnetischen Teilchen sorgt für eine schnelle Disper gierung, bei einigen Stabilisatorsubstanzen sogar schon bei leichtem Rühren mit dem Glasstab.Only the chemical binding of silanetriol and / or mercapto group-containing stabilizer substances on the surface of the superparamagnetic particles ensures a quick disper alloy, even with some stabilizer substances stir gently with a glass rod.
Je nach Anwendungsgebiet können die magnetischen Dispersionen dialysiert werden, um den überschüssigen Anteil an Stabili satorsubstanz zu entfernen.Depending on the field of application, the magnetic dispersions be dialyzed to remove the excess of stabilizers remove sator substance.
Die stabilisierten superparamagnetischen Teilchendispersionen enthalten noch nicht oder nur schwach aggregierten superpara magnetischen Eindomänenteilchen. Diese bilden eine stabile magnetische Flüssigkeit, die sich leicht von den größeren superparamagnetischen Teilchen durch eine Sedimentation in einem Magnetfeld entsprechender Stärke und Inhomogenität ab trennen lassen. Diese abgetrennten Teilchendispersionen von stabilisierten superparamagnetischen Eindomänenteilchen lassen sich gut als Kontrastmittel für die Kernspin-Diagnostik verwenden.The stabilized superparamagnetic particle dispersions contain superpara not yet or only weakly aggregated magnetic single domain particles. These form a stable magnetic liquid that differs slightly from the larger superparamagnetic particles by sedimentation in a magnetic field of appropriate strength and inhomogeneity let separate. These separated particle dispersions from stabilized superparamagnetic single domain particles can be used as a contrast medium for nuclear spin diagnostics use.
In einer einfachen Ausführung der magnetischen Separation stellt man ein Becherglas mit der magnetischen Dispersion auf einen Permanentmagneten mit einer magnetischen Flußdichte von 0,1 mT und gießt nach einer Sedimentationszeit von ca. 30 min die überstehende magnetische Flüssigkeit ab. Zurück bleiben die superparamagnetischen Teilchen, die, je nach Teilchengröße, sich wieder spontan in der Dispersion verteilen oder als Bodensatz im Becherglas zurück bleiben. Bis zu Teilchen größen von ungefähr 500 nm verteilen sich die superparamagne tischen Teilchen wieder spontan oder unter leichtem Rühren im wäßrigen Dispersionsmittel. Größere superparamagnetische Teil chen als ca. 500 nm können leicht durch stärkeres Rühren oder Ultraschallbehandlung dispergiert werden.In a simple version of the magnetic separation put up a beaker with the magnetic dispersion a permanent magnet with a magnetic flux density of 0.1 mT and pours after a sedimentation time of approx. 30 min the excess magnetic liquid. Stay back the superparamagnetic particles, which, depending on the particle size, distribute itself spontaneously in the dispersion or remain as sediment in the beaker. Up to particles sizes of approximately 500 nm are distributed in the superparamagne particles again spontaneously or with gentle stirring in the aqueous dispersant. Larger superparamagnetic part Chen than about 500 nm can easily by stirring or Ultrasonic treatment can be dispersed.
Die Sedimentationsstabilität der erfindungsgemäßen superpara magnetischen Teilchen ist wesentlich höher als bei den bisher bekannten Magnetteilchen mit vergleichbaren magnetischen Eigen schaften, was wahrscheinlich auf die starke Strukturierung der die superparamagnetischen Teilchen umgebenden Wassermoleküle und den damit vergrößerten Stokes′schen Teilchendurchmesser zurückzuführen ist.The sedimentation stability of the superpara according to the invention magnetic particles is much higher than the previous ones known magnetic particles with comparable magnetic properties what is probably due to the strong structuring of the the water molecules surrounding the superparamagnetic particles and the thus increased Stokes particle diameter is due.
Die magnetischen Eigenschaften der superparamagnetischen Teil chen bewirken, aufgrund des geringen Anteils an Stabilisator substanz, eine Kontrastverstärkung gegenüber den bisher bekann ten negativen Kontrastmitteln für die Kernspin-Diagnostik.The magnetic properties of the superparamagnetic part Chen cause, due to the low proportion of stabilizer substance, a contrast enhancement compared to the previously known negative contrast agents for MRI diagnostics.
Da der Anteil an superparamagnetischen Eindomänenteilchen wesentlich höher als bei den bisher bekannten Magnetteilchen ist, ist auch die Abscheidungsgeschwindigkeit der superpara magnetischen Teilchen in einem inhomogenen Magnetfeld größer. In einer 10 Gew.-% igen wässrigen Dispersion von superpara magnetischen Teilchen, mit einem Durchmesser von ca. 100 nm und einem Magnetanteil von 95%, beträgt die Abscheidungs zeit der Magnetteilchen auf einen Permanentmagneten mit einer magnetischen Flußdichte von 0,1 mT weniger als 1 min. Because the proportion of superparamagnetic single domain particles much higher than that of the magnetic particles known to date is also the deposition speed of the superpara magnetic particles larger in an inhomogeneous magnetic field. In a 10% by weight aqueous dispersion of superpara magnetic particles, with a diameter of approx. 100 nm and a magnetic content of 95%, is the deposition time of the magnetic particles on a permanent magnet with a magnetic flux density of 0.1 mT less than 1 min.
Die erfindungsgemäßen superparamagnetischen Teilchen haben Eisenoxidgehalte von 90 bis 98 Gew.-%. Gegenüber dem Stand der Technik, daß Magnetteilchen bis zu 50 Gew.-% Eisenoxid enthal ten können, bedeutet das eine wesentliche Verbesserung der magnetischen Eigenschaften. Damit können die neuen superpara magnetischen Teilchen, bei gleichen magnetischer Wechselwir kung, entsprechend kleiner als die bisher bekannten Magnetteil chen sein. Die spezifische Oberfläche vergrößert sich, es kön nen mehr pharmakologisch wirksame Substanzen oder gewebespezi fische Bindungssubstanzen auf der Oberfläche gekoppelt werden. Mit Verkleinerung der Teilchengröße wird auch die biologische Verträglichkeit besser, die Abbaugeschwindigkeit im Körper er höht. Auch die freie verfügbare Zeit der Magnetteilchen beim magnetischen drug targeting, d. h. die Zeit bis die Teilchen vom retikuloendothelialem System gebunden sind, erhöht sich mit Verringerung der Teilchengröße.The superparamagnetic particles according to the invention have Iron oxide contents of 90 to 98% by weight. Compared to the state of the Technology that magnetic particles contain up to 50 wt .-% iron oxide that means a significant improvement in magnetic properties. The new superpara magnetic particles, with the same magnetic interaction kung, correspondingly smaller than the previously known magnetic part be. The specific surface area increases, it can NEN more pharmacologically active substances or tissue-specific fish binding substances are coupled on the surface. As the particle size decreases, so does the biological Tolerability better, the rate of breakdown in the body increases. Also the free time of the magnetic particles at magnetic drug targeting, d. H. the time until the particles bound by the reticuloendothelial system increases with particle size reduction.
Die Bioverfügbarkeit der superparamagnetischen Teilchen im Körper beträgt, je nach Teilchengröße und Zusammensetzung der Stabilisatorsubstanzen nur wenige Minuten bis einige Stunden, d. h. das retikuloendotheliale System bindet die superpara magnetischen Teilchen relativ schnell.The bioavailability of the superparamagnetic particles in the Body is, depending on the particle size and composition of the Stabilizer substances only a few minutes to a few hours, d. H. the reticuloendothelial system binds the superpara magnetic particles relatively quickly.
An Beispielen sollen die Herstellung der erfindungsgemäßen superparamagnetischen Teilchen erläutert werden.The examples according to the invention are intended to be prepared superparamagnetic particles are explained.
Eisen(III)-chlorid (270 g) und Eisen(II)-chlorid (119 g) werden in 1 l dest. Wasser gelöst. Durch Zugabe von Ammoniakwasser wird unter Rühren der pH-Wert der Lösung auf 9,0 eingestellt. Nach erfolgter Fällung wird die Dispersion mit Salzsäure auf den pH 6,0 eingestellt und auf 100°C erwärmt. Nach dem Ab kühlen wird der Niederschlag mit dest. Wasser gewaschen, bis die elektrische Leitfähigkeit < 10 µS/cm beträgt.Iron (III) chloride (270 g) and iron (II) chloride (119 g) in 1 l dist. Water dissolved. By adding ammonia water the pH of the solution is adjusted to 9.0 with stirring. After precipitation, the dispersion is opened with hydrochloric acid adjusted the pH 6.0 and heated to 100 ° C. After the Ab the precipitate will cool with dist. Washed water until the electrical conductivity is <10 µS / cm.
Die gebildeten superparamagnetischen Teilchen bestehen aus Fe₃O₄ und können stabilisiert werden.The superparamagnetic particles formed consist of Fe₃O₄ and can be stabilized.
Eisen(III)-chlorid (270 g) und Eisen(II)-sulfat (153 g) werden in 1 l dest. Wasser gelöst. Durch Zugabe von Ammoniakwasser wird unter Rühren der pH-Wert der Lösung auf 9,0 eingestellt. Nach erfolgter Fällung wird die Dispersion unter Rühren mit Salzsäure auf pH 5,5 eingestellt und mit 20 ml einer 25%-igen Wasserstoffperoxidlösung versetzt und 30 min auf 80°C erwärmt. Nach dem Abkühlen der Dispersion wird der Niederschlag ge waschen, bis die elektrische Leitfähigkeit < 10 µS/cm beträgt. Die entstandenen superparamagnetischen Teilchen sind aus γ-Fe₂O₃ und können stabilisiert werden. Iron (III) chloride (270 g) and iron (II) sulfate (153 g) in 1 l dist. Water dissolved. By adding ammonia water the pH of the solution is adjusted to 9.0 with stirring. After precipitation, the dispersion is stirred with Hydrochloric acid adjusted to pH 5.5 and with 20 ml of a 25% Hydrogen peroxide solution added and heated to 80 ° C for 30 min. After cooling the dispersion, the precipitate is ge wash until the electrical conductivity is <10 µS / cm. The resulting superparamagnetic particles are out γ-Fe₂O₃ and can be stabilized.
Eisen (III)-chlorid (270 g) und Eisen(II)-sulfat (153 g) werden in 1 l dest. Wasser gelöst. Durch Zugabe von Natronlauge wird unter Rühren ein pH-Wert von 9,5 eingestellt. Nach erfolgter Fällung wird die Dispersion unter Rühren mit Salzsäure auf den pH-Wert von 5,0 eingestellt und auf 100°C erwärmt. Nach dem Abkühlen der Dispersion wird der Niederschlag gewaschen, bis das Filtrat eine elektrische Leitfähigkeit von < 10 µS/cm be sitzt. Das entstehende Fe₃O₄ kann stabilisiert werden. Die Sta bilisierung der superparamagnetischen Teilchen erfolgt durch Mischen einer wäßrigen oder niedrigsiedende polare Lösungsmit tel enthaltenden Stabilisatorlösung mit den Magnetteilchen bei Raumtemperatur. Die Stabilisatorlösung kann dabei, je nach den gewünschten Eigenschaften, aus reinen Stabilisatorsubstanzen oder aus Mischungen von Stabilisatorsubstanzen bestehen. Zur Beschleunigung der Dispergierung und Stabilisierung kann die Dispersion gerührt oder mit Ultraschall behandelt werden. Kom men niedrigsiedende organische Lösungsmittel zur Anwendung, werden diese zur Entfernung nach der Stabilisierung durch Vakuumverdampfung oder Dialyse entfernt.Iron (III) chloride (270 g) and iron (II) sulfate (153 g) in 1 l dist. Water dissolved. By adding sodium hydroxide solution a pH of 9.5 was set with stirring. After done The dispersion is precipitated while stirring with hydrochloric acid pH adjusted to 5.0 and heated to 100 ° C. After this Cooling the dispersion, the precipitate is washed until the filtrate has an electrical conductivity of <10 µS / cm sits. The resulting Fe₃O ent can be stabilized. The Sta bilization of the superparamagnetic particles takes place through Mixing an aqueous or low boiling polar solution with stabilizer solution containing the magnetic particles Room temperature. The stabilizer solution can, depending on the desired properties, from pure stabilizer substances or consist of mixtures of stabilizer substances. For The dispersion can be accelerated and stabilized Dispersion stirred or treated with ultrasound. Com low-boiling organic solvents are used, will remove these after stabilization Vacuum evaporation or dialysis removed.
An einigen Beispielen soll die Stabilisierung der superpara magnetischen Teilchen erläutert werden. The stabilization of the superpara magnetic particles are explained.
Die gesamte Menge des Magnetit-Niederschlages von Beispiel 1 wird in eine Lösung von 30 g Gallussäure in 400 ml dest. Was sern verrührt und 10 min mit Ultraschall von 100 W Leistung dispergiert. Die entstehende Dispersion wird 30 min auf einen Permanentmagneten mit einer magnetischen Flußdichte von 0,1 mT sedimentiert und der Überstand von magnetischer Flüssigkeit ab gesaugt. Das Sediment auf dem Magnetfeld enthält die superpara magnetischen Teilchen. Durch mehrmaliges Waschen mit dest. Was ser und erneuerter Sedimentation im Magnetfeld können die super paramagnetischen Teilchen rein und in enger Teilchengrößenver teilung erhalten werden. Die superparamagnetischen Teilchen haben einen mittleren Teilchendurchmesser von 120 nm.The total amount of magnetite deposit from Example 1 is in a solution of 30 g of gallic acid in 400 ml of dist. What stirred and 10 min with ultrasound of 100 W power dispersed. The resulting dispersion is 30 minutes on a Permanent magnets with a magnetic flux density of 0.1 mT sedimented and the supernatant from magnetic liquid sucked. The sediment on the magnetic field contains the superpara magnetic particles. By washing several times with dist. What This and renewed sedimentation in the magnetic field can do great paramagnetic particles pure and in narrow particle size ver division can be obtained. The superparamagnetic particles have an average particle diameter of 120 nm.
Diese superparamagnetischen Teilchen sind sehr gut für die magnetische Anreicherung in Tumoren geeignet. Hier können sie durch magnetomechanische Immunstimulierung, oder zusätzlich durch Hyperthermie, d. h. durch Einstrahlung elektromagnetischer Strahlung und Erwärmung des Tumors, den Tumor zerstören. Die superparamagnetischen Teilchen sind auch als orales oder i.v. Kontrastmittel für die Kernspin-Diagnostik anwendbar. These superparamagnetic particles are very good for that magnetic accumulation in tumors. Here you can by magnetomechanical immune stimulation, or in addition through hyperthermia, d. H. by electromagnetic radiation Radiation and warming of the tumor, destroy the tumor. The superparamagnetic particles are also known as oral or IV. Contrast agent for nuclear spin diagnostics applicable.
Die gesamte Menge des γ-Fe₂O₃-Niederschlages von Beispiel 2 wird in eine Lösung von 20 g Rutinosid in 300 ml Methanol ge geben und 5 min mit Ultraschall von 100 W Leistung dispergiert. Anschließend wird zur Dispersion 500 ml dest. Wasser gegeben und das Methanol abdestilliert. Die wäßrige Dispersion wird nochmals 20 min mit Ultraschall von 100 W Leistung dispergiert. Die Abtrennung der nicht oder nur schwach agglomerierten super paramagnetischen Eindomänenteilchen, die eine stabile magne tische Flüssigkeit bilden, erfolgt durch eine magnetische Sedi mentation wie im Beispiel 4 beschrieben.The total amount of γ-Fe₂O₃ precipitate from Example 2 is ge in a solution of 20 g of rutinoside in 300 ml of methanol give and dispersed for 5 min with ultrasound of 100 W power. Then 500 ml of dist. Given water and the methanol was distilled off. The aqueous dispersion is dispersed again with ultrasound of 100 W power for 20 min. The separation of the super or not agglomerated weakly paramagnetic single domain particles that have a stable magne Form a table liquid by means of a magnetic sedi mentation as described in Example 4.
Die entstehenden superparamagnetischen Teilchen haben einen mittleren Teilchendurchmesser von 160 nm und sind für die Kopp lung von aminosäurehaltigen gewebespezifischen Bindungssubstan zen, pharmakologisch wirksamen Substanzen und pharmakologisch wirksamen Zellen geeignet.The resulting superparamagnetic particles have one average particle diameter of 160 nm and are for the Kopp treatment of tissue-specific binding substances containing amino acids zen, pharmacologically active substances and pharmacologically effective cells.
20 ml der Dispersion von Beispiel 5, mit einer magnetischen Sättigungsinduktion von 10 mT, werden mit einer Lösung von 10 mg Doxorubicin in 10 ml physiologische Kochsalzlösung gemischt. Diese superparamagnetischen Teilchen sind sehr gut für die magnetische Anreicherung in Tumoren geeignet. Hier können sie durch die Wirkung des Zytostatikum zur Tumorschädigung führen. 20 ml of the dispersion of Example 5, with a magnetic Saturation induction of 10 mT, with a solution of 10 mg doxorubicin mixed in 10 ml of physiological saline. These superparamagnetic particles are very good for that magnetic accumulation in tumors. Here you can lead to tumor damage due to the action of the cytostatic.
Die gesamte Menge des Magnetit-Niederschlages von Beispiel 3 wird in eine Lösung von 30 g Tanninsäure in 500 ml Wasser ge geben und 20 min mit einem Ultraschalldispergator (100 W Lei stung), unter Erwärmen auf 70°C, dispergiert. Die entstehende Dispersion wird mit einem 50 kD-Filter gegen dest. Wasser dia lysiert, um überschüssige Stabilisatorsubstanzen zu entfernen. Die Abtrennung der nicht oder nur schwach agglomerierten super paramagnetischen Eindomänenteilchen, die eine stabile magne tische Flüssigkeit bilden, erfolgt durch eine magnetische Sedimentation wie im Beispiel 3 beschrieben.The total amount of magnetite precipitate from Example 3 is ge in a solution of 30 g of tannic acid in 500 ml of water give and 20 min with an ultrasonic disperser (100 W Lei stung), while heating to 70 ° C, dispersed. The emerging Dispersion is with a 50 kD filter against dest. Water dia lysed to remove excess stabilizer substances. The separation of the super or not agglomerated weakly paramagnetic single domain particles that have a stable magne table liquid is formed by a magnetic Sedimentation as described in Example 3.
Die entstehenden superparamagnetischen Teilchen haben einen mittleren Teilchendurchmesser von 210 nm und sind für die Kopp lung von aminosäurehaltigen gewebespezifischen Bindungssubstan zen, pharmakologisch wirksamen Substanzen und pharmakologisch wirksamen Zellen geeignet.The resulting superparamagnetic particles have one average particle diameter of 210 nm and are for the Kopp treatment of tissue-specific binding substances containing amino acids zen, pharmacologically active substances and pharmacologically effective cells.
An die mit aromatischer Tanninsäure stabilisierten superpara magnetischen Teilchen lassen sich auch diamagnetische aroma tische pharmakologisch wirksame Substanzen adsorptiv binden, wobei letztere Substanzen beim magnetischen drug targeting, unter der Einwirkung eines inhomogenen Magnetfeldes, wieder von der Oberfläche der superparamagnetischen Teilchen desorbiert werden. Erfolgt eine adsorptive Bindung von z. B. zytostatisch wirksamen Anthrachinonen, wie z. B. Mitoxantron, an Teilchen nach Beispiel 7, so kann dieses Produkt für ein magnetisches drug targeting von Zytostatika in der Tumortherapie eingesetzt werden. To the superpara stabilized with aromatic tannic acid Magnetic particles can also have diamagnetic aroma bind pharmacologically active substances adsorptively, the latter substances in magnetic drug targeting, under the influence of an inhomogeneous magnetic field, again from desorbed the surface of the superparamagnetic particles will. If an adsorptive binding of z. B. cytostatic effective anthraquinones, such as. B. Mitoxantron, on particles according to Example 7, this product can be used for a magnetic drug targeting of cytostatics used in tumor therapy will.
20 ml der Dispersion von Beispiel 7, mit einer magnetischen Sättigungsinduktion von 10 mT, werden mit einer Lösung von 10 mg Mitoxantron in 10 ml einer acetatgepufferten physiologische Kochsalzlösung gemischt.20 ml of the dispersion of Example 7, with a magnetic Saturation induction of 10 mT, with a solution of 10 mg mitoxantrone in 10 ml of an acetate-buffered physiological Saline mixed.
Diese superparamagnetischen Teilchen sind sehr gut für die magnetische Anreicherung in Tumoren geeignet. Hier können sie durch die magnetische Anreicherung im Tumor und die verstärkte Desorption des Zytostatikums unter der Wirkung des inhomogenen Magnetfeldes zur Tumorschädigung führen.These superparamagnetic particles are very good for that magnetic accumulation in tumors. Here you can due to the magnetic accumulation in the tumor and the increased Desorption of the cytostatic under the action of the inhomogeneous Magnetic field lead to tumor damage.
Die gesamte Menge des Magnetit-Niederschlages von Beispiel 1 wird in eine Lösung von 25 g einer basisch aufgeschlossenen 80° Bloom Gelatine von in 500 ml dest. Wasser gut verrührt und 20 min mit einem Ultraschalldispergator (100 W Leistung) disper giert. Die entstehende Dispersion wird mit einem 50 kD-Filter gegen dest. Wasser dialysiert, um überschüssige Stabilisator substanzen zu entfernen. Die Abtrennung der nicht oder nur schwach agglomerierten superparamagnetischen Eindomänenteil chen, die eine stabile magnetische Flüssigkeit bilden, erfolgt durch eine magnetische Sedimentation wie im Beispiel 3 be schrieben.The total amount of magnetite deposit from Example 1 is in a solution of 25 g of a basic digested 80 ° Bloom gelatin from 500 ml dist. Water mixed well and 20 min with an ultrasonic disperser (100 W power) yaws. The resulting dispersion is with a 50 kD filter against dest. Water dialyses to excess stabilizer remove substances. The separation of not or only weakly agglomerated superparamagnetic single domain Chen, which form a stable magnetic liquid takes place by magnetic sedimentation as in Example 3 wrote.
Die superparamagnetischen Teilchen haben einen mittleren Teil chendurchmesser von 120 nm. The superparamagnetic particles have a middle part diameter of 120 nm.
Die nach Beispiel 9 hergestellten superparamagnetischen Teil chen sind für viele Kopplungsreaktionen verwendbar, bei denen die Reaktivität der aminosäuregruppenhaltigen Stabilisatorsub stanzen Anwendung finden kann. Diese Kopplungsreaktionen sind Stand der Technik.The superparamagnetic part produced according to Example 9 Chen can be used for many coupling reactions in which the reactivity of the stabilizer sub containing amino acid groups stamping can be used. These are coupling reactions State of the art.
Die gesamte Menge des Magnetit-Niederschlages von Beispiel 1 wird in eine Lösung von 40 ml einer 30%-igen Natriumsilikat lösung in 500 ml dest. Wasser gegeben, 5 min gerührt und 10 min mit einem Ultraschalldispergator (100 W Leistung) dispergiert. Die entstehende Dispersion wird mit einer 10 gew.-%igen Gallussäure-Lösung auf einen pH-Wert von 7,0 titriert, 10 min mit einem Ultraschalldispergator (100 W Leistung) dispergiert und 30 min auf einen Permanentmagneten mit einer magnetischen Flußdichte von 0,1 T sedimentiert und der Überstand von magne tischer Flüssigkeit abgesaugt. Das Sediment auf dem Magnetfeld enthält die superparamagnetischen Teilchen. Durch mehrmaliges Waschen mit dest. Wasser und erneuert Sedimentation im Magnet feld können die superparamagnetischen Teilchen rein und in enger Teilchengrößenverteilung erhalten werden. Die superpara magnetischen Teilchen haben einen mittleren Teilchendurchmesser von 120 nm und sind für die Kopplung von aminosäurehaltigen ge webespezifischen Bindungssubstanzen, pharmakologisch wirksamen Substanzen und pharmakologisch wirksamen Zellen geeignet. The total amount of magnetite deposit from Example 1 is in a solution of 40 ml of a 30% sodium silicate solution in 500 ml dist. Water, stirred for 5 min and 10 min dispersed with an ultrasonic disperser (100 W power). The resulting dispersion is with a 10 wt .-% Gallic acid solution titrated to pH 7.0, 10 min dispersed with an ultrasonic disperser (100 W power) and 30 min on a permanent magnet with a magnetic Sediment flux density of 0.1 T and the supernatant of magne aspirated liquid. The sediment on the magnetic field contains the superparamagnetic particles. By repeated Wash with dist. Water and renewed sedimentation in the magnet the superparamagnetic particles can enter and leave the field narrow particle size distribution can be obtained. The superpara magnetic particles have an average particle diameter of 120 nm and are for the coupling of amino acid ge weave-specific binding substances, pharmacologically active Suitable substances and pharmacologically active cells.
Die im Magnetfeld abgetrennte magnetische Flüssigkeit aus superparamagnetischen Eindomänenteilchen kann als Kontrastmit tel für die Kernspin-Diagnostik-zur Darstellung der Blutgefäße verwendet werden.The magnetic liquid separated in the magnetic field superparamagnetic single domain particles can be used as a contrast tel for MRI diagnostics - to visualize the blood vessels be used.
Die gesamte Menge des Magnetit-Niederschlages von Beispiel 2 wird in eine Lösung von 40 ml einer 40%-igen Phytinsäurelösung in 500 ml dest. Wasser gegeben, 5 min gerührt und 10 min mit einem Ultraschalldispergator (100 W Leistung) dispergiert. Die entstehende Dispersion wird mit einer 30%-igen Natriumsilikat lösung auf einen pH-Wert von 7,0 titriert, 10 min mit einem Ultraschalldispergator (100 W Leistung) dispergiert und 30 min auf einen Permanentmagneten mit einer magnetischen Flußdichte von 0,1 T sedimentiert und der Überstand von magnetischer Flüs sigkeit abgesaugt. Das Sediment auf dem Magnetfeld enthält die superparamagnetischen Teilchen. Durch mehrmaliges Waschen mit dest. Wasser und erneuert Sedimentation im Magnetfeld können die superparamagnetischen Teilchen rein und in enger Teilchen größenverteilung erhalten werden. Die superparamagnetischen Teilchen haben einen mittleren Teilchendurchmesser von 160 nm und sind für die Kopplung von aminosäurehaltigen gewebespezi fischen Bindungssubstanzen, pharmakologisch wirksamen Substan zen und pharmakologisch wirksamen Zellen geeignet. The total amount of magnetite precipitate from Example 2 is in a solution of 40 ml of a 40% phytic acid solution in 500 ml dist. Water was added, stirred for 5 min and with for 10 min dispersed in an ultrasonic disperser (100 W power). The resulting dispersion is with a 30% sodium silicate solution titrated to pH 7.0, 10 min with a Ultrasonic disperser (100 W power) dispersed and 30 min on a permanent magnet with a magnetic flux density sedimentation of 0.1 T and the supernatant of magnetic fluxes aspirated liquid. The sediment on the magnetic field contains the superparamagnetic particles. By washing it several times least Water and renewed sedimentation in the magnetic field can the superparamagnetic particles pure and in narrow particles size distribution can be obtained. The superparamagnetic Particles have an average particle diameter of 160 nm and are for the coupling of amino acid-containing tissue speci fish binding substances, pharmacologically active substance zen and pharmacologically active cells.
Das Hauptanwendungsgebiet der erfindungsgemäßen superparamagne tischen Teilchen liegt auf dem Gebiet des magnetischen drug targeting. Aufgrund der sehr hohen Anteiles an Magnetmaterial (90 bis 98 Gew.-%) lassen sich schon kleine Magnetteilchen sehr gut und sehr schnell in bestimmte Regionen des Körpers mit Hilfe von elektromagnetischen oder Permanentmagnet-Feldern kon zentrieren. Bei Kopplung von pharmakologisch wirksamen Substan zen an die superparamagnetischen Teilchen, kann deren Konzen tration am Wirkungsort drastisch erhöht werden. Dieser Umstand hat für die Krebstherapie besondere Bedeutung, da die zur Che motherapie von Tumoren eingesetzten Substanzen sehr starke Nebenwirkungen auf den gesamten Organismus ausüben und bei einer Anreicherung am Wirkungsort der übrige Körper weniger stark mit Zytostatika belastet wird.The main area of application of the superparamagne according to the invention table particle is in the field of magnetic drug targeting. Due to the very high proportion of magnetic material (90 to 98% by weight) even small magnetic particles can be very well and very quickly into certain regions of the body With the help of electromagnetic or permanent magnet fields center. When coupling pharmacologically active substances zen to the superparamagnetic particles, can concentrate them tration at the site of action. This condition is of particular importance for cancer therapy, since it is used for Che Motherotherapy of substances used in tumors is very strong Side effects on the entire organism and exert an accumulation at the site of action of the remaining body less is heavily burdened with cytostatics.
Die superparamagnetischen Teilchen können durch Kopplung an Viren, Zellen und deren Oberflächenmolekülen zur Immunaktivie rung im Körper eingesetzt werden, wobei die Einwirkung von Magnetfeldern die Immunaktivierung unterstützt.The superparamagnetic particles can be coupled Viruses, cells and their surface molecules for immune activation tion in the body, the action of Magnetic fields that support immune activation.
Die superparamagnetischen Teilchen können auch als Kontrast mittel für Kernspin-Diagnostik eingesetzt werden.The superparamagnetic particles can also be used as a contrast can be used for MRI diagnostics.
Die Konzentration der einzusetzenden superparamagnetischen Teilchen ist beim magnetischen drug targeting abhängig von der Teilchengröße, von der Zusammensetzung der Stabilisatorsubstan zen, von der magnetischen Feldstärke am Wirkungsort und wie groß die Entfernung von der Injektionsstelle zum Wirkungsort ist. The concentration of the superparamagnetic to be used In magnetic drug targeting, particle is dependent on the Particle size, from the composition of the stabilizer substance zen, the magnetic field strength at the place of action and how large the distance from the injection site to the site of action is.
Um eine Nekrose eines Tumores bei Nacktmäusen zu erreichen, ist eine Menge an Injektionsflüssigkeit von ca. 0,01 bis 0,2 Vol-% des Blutvolumens notwendig, wobei die magnetischen Sättigungs induktion bei ca. 5 mT liegt.To achieve necrosis of a tumor in nude mice is a quantity of injection liquid of approx. 0.01 to 0.2 vol% of blood volume necessary, taking the magnetic saturation induction is approx. 5 mT.
Die Mengen an superparamagnetischen Teilchen liegen bei der An wendung als Kontrastmittel für die MRI bei ca. 0,001 Vol-% des Blutvolumens, wenn die magnetische Sättigungsinduktion bei ca. 5 mT liegt.The quantities of superparamagnetic particles are at the An used as a contrast medium for MRI at approx. 0.001 vol% of the Blood volume if the magnetic saturation induction at approx. 5 mT is.
Die erfindungsgemäßen superparamagnetischen Teilchen können als orale und parenterale Kontrastmittel für die Kernspin-Diagno stik eingesetzt werden.The superparamagnetic particles according to the invention can be used as oral and parenteral contrast media for nuclear spin diagnosis be used stik.
Die reaktiven superparamagnetischen Teilchen können auch zur in vitro Diagnostik eingesetzt werden, wenn auf der Oberfläche der Teilchen die entsprechenden diagnostischen Substanzen gebunden werden. Aufgrund der starken magnetischen Wechselwirkung der superparamagnetischen Teilchen mit Magnetfeldern, lassen sich noch sehr kleine superparamagnetische Teilchen nach erfolgter diagnostischer Reaktion leicht aus dem Reaktionsgemisch wieder abtrennen.The reactive superparamagnetic particles can also be used in vitro diagnostics are used when on the surface of the Particles bound the corresponding diagnostic substances will. Due to the strong magnetic interaction of the superparamagnetic particles with magnetic fields, can be very small superparamagnetic particles after diagnostic reaction easily from the reaction mixture again split off.
Claims (11)
- (a) stabilen, abbaubaren Aggregaten mit einer Teilchengröße im Bereich zwischen 10 und 1000 Nanometer mit definiertem Verhal ten im Magnetfeld, wobei die Aggregate
- (b) aus mehreren kleinen superparamagnetischen Eindomänenteil
chen aus Eisenoxid-, Eisenmischoxid- oder Eisen mit einer Teil
chengröße im Bereich zwischen 3 und 20 Nanometer bestehen, nach
Patent (Patentanmeldung P 43 09 333.7),
dadurch gekennzeichnet, daß sie - (c) auf ihrer Oberfläche Substanzen der Gruppe der
- (i) mono- und/oder polyhydroxylgruppenhaltigen aromatischen Substanzen, ausgewählt unter Benzenoiden, Cumarinen, Lignanen, Terphenylen, Flavonoiden, Tanninen, Xanthonen, Benzophenonen, Naphthalenen, Naphthochinonen, Anthrachinonen, Anthracyclinen, polycyclische kondensierte aromatische Verbindungen und deren phosphat-, diphosphat-, polyphosphat-, thiophosphat-, phos phonat-, thiophosphonat-, carboxylat-, sulfat-, mercapto- oder silantriolgruppenhaltigen Derivaten, und/oder
- (ii) aminosäurenhaltigen Substanzen, ausgewählt unter schwefel haltigen Aminosäuren, Oligopeptiden, Polypeptiden, Proteinen, Proteiden sowie deren Denaturierungsprodukten, gebunden tragen, die weitere Bindungsstellen aufweisen können und/oder
- (iii) den silikatgruppenhaltigen Substanzen der Orthokiesel säure und deren Kondensationsprodukten mit zwei und mehrwerti gen anorganischen Ionen und/oder organischen Säuren und Basen gebunden tragen.
- (a) stable, degradable aggregates with a particle size in the range between 10 and 1000 nanometers with defined behavior in the magnetic field, the aggregates
- (b) consist of several small superparamagnetic single domain particles made of iron oxide, mixed iron oxide or iron with a particle size in the range between 3 and 20 nanometers, according to patent (patent application P 43 09 333.7),
characterized in that they - (c) substances of the group of
- (i) aromatic substances containing mono- and / or polyhydroxyl groups, selected from benzenoids, coumarins, lignans, terphenyls, flavonoids, tannins, xanthones, benzophenones, naphthalenes, naphthoquinones, anthraquinones, anthracyclines, polycyclic condensed aromatic compounds and their phosphate, diphosphate polyphosphate, thiophosphate, phosphate, thiophosphonate, carboxylate, sulfate, mercapto or silanetriol group-containing derivatives, and / or
- (ii) Bound amino acid-containing substances, selected from sulfur-containing amino acids, oligopeptides, polypeptides, proteins, proteids and their denaturing products, which may have further binding sites and / or
- (Iii) wear the silicate group-containing substances of orthosilicic acid and their condensation products bound with two and polyvalent inorganic ions and / or organic acids and bases.
- (i) eine gewebespezifische Bindungssubstanz aus der Gruppe der Antigene, Antikörper, Ribonucleinsäuren, Desoxyribonucleinsäu ren, Ribonucleinsäuresequenzen, Desoxyribonucleinsäuresequen zen, Haptene, Protein A, Protein G, Endotoxinbindende Proteine, Lectine, Selectine;
- (ii) eine pharmakologisch wirksame Substanze aus der Gruppe der Antitumorproteine, Enzyme, Antitumorenzyme, Antibiotika, Pflanzenalkaloide, Alkylierungsreagenzien, Antimetaboliten, Hormone und Hormonantagonisten, Interleukine, Interferone, Wachstumsfaktoren, Tumdrnekrosefaktoren, Endotoxine, Lympho toxine, Urokinase, Streptokinase, Plasminogen-Streptokinase- Aktivator-Komplex, Gewebe-Plasminogen-Aktivatoren, Desmodus- Plasminogen-Aktivatoren, Makrophagen-Aktivierungskörper, Anti sera, Proteaseninhibitoren, radioakiven Phosphor 32P enthaltene Stabilisatorsubstanzen, Tenside, kardiovaskulare Pharmazeutika, Chemotherapeutika, gastrointestinale Pharmazeutika, Neurophar mazeutika,
- (iii) pharmakologisch wirksame Zellen aus der Gruppe der Orga nellen, Viren, Mikroben, Algen, Pilzen, insbesondere Erythro zyten, Thrombozyten, Granulozyten, Monozyten, Lymphozyten, Langerhans′sche Inseln;
- (iv) pharmakologisch wirksamer Komplexbildner aus der Gruppe der Polycarbonsäuren, Aminocarboxylsäuren, Porphyrinen, Katecholamine;
- (v) zellfusionvermittelnde Substanzen aus der Gruppe der Poly ethylenglykole, Alkyl-aryl-polyethylenglykole;
- (vi) Pyrophosphorsäure, Pyrophosphorsäureester, Polyphosphor säureester und deren Salze gebunden sind.
- (i) a tissue-specific binding substance from the group of antigens, antibodies, ribonucleic acids, deoxyribonucleic acids, ribonucleic acid sequences, deoxyribonucleic acid sequences, haptens, protein A, protein G, endotoxin-binding proteins, lectins, selectins;
- (ii) a pharmacologically active substance from the group of antitumor proteins, enzymes, antitumor enzymes, antibiotics, plant alkaloids, alkylation reagents, antimetabolites, hormones and hormone antagonists, interleukins, interferons, growth factors, tumor necrosis factors, endotoxins, lympho toxins, streptokinase, urogeninase, urokinase, urokinase, urokinase, urokinase, urokinase, urokinase, Activator complex, tissue plasminogen activators, desodus plasminogen activators, macrophage activation bodies, anti sera, protease inhibitors, radioactive phosphorus 32P containing stabilizer substances, surfactants, cardiovascular pharmaceuticals, chemotherapeutics, gastrointestinal pharmaceuticals, neuropharmaceuticals,
- (iii) pharmacologically active cells from the group of organs, viruses, microbes, algae, fungi, in particular erythrocytes, thrombocytes, granulocytes, monocytes, lymphocytes, Langerhans islands;
- (iv) pharmacologically active complexing agents from the group of polycarboxylic acids, aminocarboxylic acids, porphyrins, catecholamines;
- (v) cell fusion-mediating substances from the group of poly ethylene glycols, alkyl-aryl-polyethylene glycols;
- (vi) pyrophosphoric acid, pyrophosphoric acid ester, polyphosphoric acid ester and their salts are bound.
- (i) mono- und polyhydroxylgruppenhaltige aromatische Substan zen, ausgewählt unter Benzenoiden, Cumarinen, Lignanen, Terphenylen, Flavonoiden, Tanninen, Xanthonen, Benzophenonen, Naphthalenen, Naphthochinonen, Anthrachinonen, Anthracyclinen, polycyclische kondensierte aromatische Verbindungen und deren phosphat-, diphosphat-, polyphosphat-, thiophosphat-, phos phonat-, thiophosphonat-, carboxylat-, sulfat-, mercapto- oder silantriolgruppenhaltigen Derivaten,
- (ii) silikatgruppenhaltige Substanzen der Orthokieselsäure und deren Kondensationsprodukte mit zwei und mehrwertigen anorgani schen Ionen und/oder organischen Säuren und Basen gebunden tragen.
- (i) Aromatic substances containing mono- and polyhydroxyl groups, selected from benzenoids, coumarins, lignans, terphenyls, flavonoids, tannins, xanthones, benzophenones, naphthalenes, naphthoquinones, anthraquinones, anthracyclines, polycyclic condensed aromatic compounds and their phosphate, polyphosphate, diphosphate -, thiophosphate, phos phonate, thiophosphonate, carboxylate, sulfate, mercapto or silanetriol group-containing derivatives,
- (ii) wearing silicate group-containing substances of orthosilicic acid and their condensation products bound with two and polyvalent inorganic ions and / or organic acids and bases.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4427821A DE4427821A1 (en) | 1993-03-17 | 1994-07-27 | Stabilised super-paramagnetic aggregate particles |
| PCT/DE1995/001028 WO1996003653A1 (en) | 1994-07-27 | 1995-07-27 | Superparamagnetic particles, process for their production and their use |
| AT95927635T ATE191086T1 (en) | 1994-07-27 | 1995-07-27 | SUPERPARAMAGNETIC PARTICLES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| EP95927635A EP0772776B1 (en) | 1994-07-27 | 1995-07-27 | Superparamagnetic particles, process for their production and their use |
| US08/776,131 US5928958A (en) | 1994-07-27 | 1995-07-27 | Superparamagnetic particles, process for their manufacture and usage |
| DE59508069T DE59508069D1 (en) | 1994-07-27 | 1995-07-27 | SUPERPARAMAGNETIC PARTICLES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| JP50536896A JP3436760B2 (en) | 1994-07-27 | 1995-07-27 | Superparamagnetic particles |
| US09/300,532 US6274121B1 (en) | 1994-07-27 | 1999-04-27 | Superparamagnetic particles, process for their manufacture and use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4309333A DE4309333A1 (en) | 1993-03-17 | 1993-03-17 | Superparamagnetic particles, process for their production and use thereof |
| DE4427821A DE4427821A1 (en) | 1993-03-17 | 1994-07-27 | Stabilised super-paramagnetic aggregate particles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE4427821A1 true DE4427821A1 (en) | 1996-02-01 |
Family
ID=6483578
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4309333A Withdrawn DE4309333A1 (en) | 1993-03-02 | 1993-03-17 | Superparamagnetic particles, process for their production and use thereof |
| DE4407338A Withdrawn DE4407338A1 (en) | 1993-03-02 | 1994-03-02 | Superparamagnetic particles and their use |
| DE4427821A Withdrawn DE4427821A1 (en) | 1993-03-17 | 1994-07-27 | Stabilised super-paramagnetic aggregate particles |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4309333A Withdrawn DE4309333A1 (en) | 1993-03-02 | 1993-03-17 | Superparamagnetic particles, process for their production and use thereof |
| DE4407338A Withdrawn DE4407338A1 (en) | 1993-03-02 | 1994-03-02 | Superparamagnetic particles and their use |
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| DE (3) | DE4309333A1 (en) |
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Also Published As
| Publication number | Publication date |
|---|---|
| DE4309333A1 (en) | 1994-09-22 |
| DE4407338A1 (en) | 1995-09-07 |
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