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EP0773796A1 - Eisen enthaltende nanopartikel mit doppeltem coating und anwendung in der diagnostik und therapie - Google Patents

Eisen enthaltende nanopartikel mit doppeltem coating und anwendung in der diagnostik und therapie

Info

Publication number
EP0773796A1
EP0773796A1 EP95924859A EP95924859A EP0773796A1 EP 0773796 A1 EP0773796 A1 EP 0773796A1 EP 95924859 A EP95924859 A EP 95924859A EP 95924859 A EP95924859 A EP 95924859A EP 0773796 A1 EP0773796 A1 EP 0773796A1
Authority
EP
European Patent Office
Prior art keywords
iron
nanoparticles
polymer
synthesis
metal ions
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.)
Ceased
Application number
EP95924859A
Other languages
German (de)
English (en)
French (fr)
Inventor
Mayk Kresse
Detlev Pfefferer
Rüdiger Lawaczek
Susanne Wagner
Wolfgang Ebert
Volker Elste
Wolfhard Semmler
Matthias Taupitz
Josef Gaida
Anja Herrmann
Monika Jukl
Udo Swiderski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Institut fuer Diagnostikforschung GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institut fuer Diagnostikforschung GmbH filed Critical Institut fuer Diagnostikforschung GmbH
Publication of EP0773796A1 publication Critical patent/EP0773796A1/de
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
    • A61K49/1824—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 coated or functionalised nanoparticles
    • A61K49/1827—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 coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—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 coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1863—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 coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
    • 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
    • A61K49/1824—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 coated or functionalised nanoparticles
    • A61K49/1827—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 coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1866—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 coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/12—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar
    • G01N2400/14—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar alpha-D-Glucans, i.e. having alpha 1,n (n=3,4,6) linkages between saccharide units, e.g. pullulan
    • G01N2400/22—Dextran
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2446/00—Magnetic particle immunoreagent carriers
    • G01N2446/20—Magnetic particle immunoreagent carriers the magnetic material being present in the particle core
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2446/00—Magnetic particle immunoreagent carriers
    • G01N2446/30—Magnetic particle immunoreagent carriers the magnetic material being dispersed in the polymer composition before their conversion into particulate form

Definitions

  • the present invention relates to modular iron-containing nanoparticles, their production and use in diagnostics and therapy.
  • the superparamagnetic iron oxides which are to be used as MR contrast agents show comparable properties in that they show a strong influence on the proton relaxation in their immediate vicinity (high relaxivity) and that they are particles with a "magnetite-like" crystal structure. Numerous processes for producing iron-containing crystals (iron oxides) with superparamagnetic properties have been described.
  • the different methods can be classified from different points of view.
  • the production of the crystals containing superparamagnetic iron distinguishes two basic processes, namely the sintering process at high temperature and subsequent mechanical comminution and the wet-chemical process
  • the iron-containing core (iron oxide) is first produced and then a stabilizer is added to ensure the physical-galenical quality.
  • a variant of the “two-pot synthesis” is the production of the iron core on ion exchangers.
  • the iron oxides are produced in the presence of the stabilizer, which already coats the cores during the precipitation of the iron salts and thus prevents the aggregation and sedimentation of the particles.
  • Magnetic iron oxides which are to be used as contrast agents in human diagnostics, require an aqueous dispersion medium for medical-toxicological reasons.
  • a special position in this classification is given to the particles, which were produced in a non-aqueous solvent, but which can be stably dispersed in an aqueous medium after production.
  • Such particles are currently generally used in ex vivo diagnostics, e.g. B. in magnetic separation technology [Chagnon MS, Groman EV, Josephson L, et al. ; US 4,554,088], but were also proposed for in vivo diagnostics [Pilgrimm H; US 5,160,725].
  • the pharmaceutically more stable suspensions / solutions of particles which were produced by the "one-pot process" in aqueous media, can also be further reduced. divide into different sized iron oxides.
  • Biotechnical applications have been proposed for the particles in the micrometer range [Schröder U, Mosbach K; WO 83/01738 or Schröder U; WO 83/03426] or even claims in vivo use in diagnostics or therapy [Widder KJ, Senyei AE; US 4,247,406 or Jacobsen T, Klaveness J; WO 85/04330].
  • For medical diagnostic approaches however, only the particles in the nanometer range are described today.
  • the nanometer range can also be divided into “large”(approx.> 50 nm total diameter) and “small” (approx. ⁇ 50 nm total diameter) particles.
  • the main area of application of the large nanometer particles today is the use in MR diagnostics of the liver and spleen, since particles of this size are quickly and almost completely absorbed by the macrophages of these organs [Kresse M, Pfefferer D, Lawaczeck R; EP 516,252 A2 or Groman EV, Josephson L; US 4,770,183].
  • suggestions have been made for use as enhancer substances in clinical hyperthermia [Hasegawa M, Hirose K, Hokukoku S, et al. ; WO 92/22586 AI and Gordon RT; US 4,731,239].
  • the precise synthesis conditions such as the type of iron salts, temperature, shell polymer (stabilizer), titration speed, choice of alkali, cleaning, etc. influence the chemical-physical properties and thus the pharmaceutical-pharmaceutical quality and ultimately the medical benefit.
  • MIONs in which the dextran shell of the particles (magnetic label) is oxidized with periodate and then coupled with specific molecules (antimyosin; polyclonal antibody) [Weissleder R, Lee AS, Khaw BA et al. ; Radiology 182; 381-385; 1992 or Weissleder R, Lee AS, Fishman A et al. ; Radiology 181; 245-249; 1991].
  • Menz et al. [Menz ET, Rothenberg JM, Groman EV, et al. ; WO 90/01295] which their large nanometer particles by polymers (arabinogalactan) envelop with physiological effector cells and, like Gordon, who oxidizes his dextran-stabilized particles with periodate and then couples transferrin by reductive amination [Gordon RT; US 4,735,796], claim a specific uptake mechanism via receptor-mediated endocytosis.
  • Stabilizer substances making whole groups more important and highly specific molecules (proteins, peptides, oligonucleotides but also most oligo- and polysaccharides) cannot be used for stabilization during production, at least not if the stabilizers after synthesis still have target properties ( biological activity).
  • a major problem in the development of specific diagnostics is the small size of the target organ. So represent z.
  • a problem with this class of substances is the crystal nucleus of the iron oxides, which determines the particulate character of the substances and the particle size has a significant influence on the biological behavior. Smaller particle sizes improve that
  • the object of the invention is to provide iron-containing nanoparticles which optimally meet the requirements of physics and biology for a specific nanoparticle.
  • the nanoparticles according to the invention are superior to the previous iron oxide particles according to the prior art with regard to the targetability.
  • contrast agents or also therapeutic agents / therapeutic carrier systems with previously unattainable "targetability” can be produced.
  • the nanoparticles are produced from individual building blocks (modular principle) and thus ensure maximum flexibility in the combination of the iron-containing cores (physical effectiveness; contrast) with the target component (biological behavior).
  • a modular structure has the advantage of combining a storable component (iron-containing core) with possibly sensitive molecules for control only "just in time” to form the finished nanoparticle.
  • This reference to the "cold kits” known from clinical radiopharmaceuticals makes it possible, for. B. also using individual serum components of individual patients as control molecules (eg autologous antibodies).
  • the nanoparticles Due to their intense coloring, it is also possible to visually detect the nanoparticles, as is the case, for example, with B. is desirable when used as an optical marker in surgical medicine.
  • the nanoparticles are also suitable for use in therapy, e.g. B. by magnetic targeting with external magnets above a target volume, combined with a magnetically coupled release of active substances, suitable.
  • the nanoparticles can in z. B. tumors are accumulated and therefore enable use as specific enhancer substances in local hyperthermia.
  • the nanoparticles according to the invention consist of an iron-containing core, a primary coat (synthesis polymer) and a secondary coat (target polymer) and optionally pharmaceutical auxiliaries, pharmaceuticals and / or adsorption mediators.
  • the iron-containing core is present as a particle, colloid or crystal.
  • the nanoparticles contain synthetic polymer, which envelops the core as a primary coat and is required during production to control the physical or pharmaceutical-pharmaceutical quality.
  • the ratio of synthetic polymer to iron is then adjusted to a desired value by means of a desorption process. For use in specific diagnostics, a
  • Adsorbed target polymer which represents the surface of the nanoparticles and envelops the basic building block of core and primary coat.
  • Adsorption mediators can be included to improve the adsorption between the primary and secondary coats.
  • the nanoparticles can contain constituents of pharmaceutical auxiliaries or pharmaceuticals.
  • FIG. 1 A schematic representation of the structure of a nanoparticle according to the invention is shown in FIG. 1.
  • the hydrodynamic diameter of the basic building block (iron-containing core and primary coat) in solution is less than 100 nm, preferably less than 50 nm, and at most five times the diameter of the core containing iron.
  • the nanoparticles according to the invention are further characterized in that they are in the form of stable colloidal sols of pharmaceutical quality, or in that they are lyophilized and easily mixed with medically used solvents (electrolyte solution, plasma expander, glucose solution, physical saline solution, etc.). can be brought back into solution or that the basic building block and target component and optionally additives are separate solutions, which can also be in the form of lyophilisates, and are only mixed together at any time to form the application solution.
  • medically used solvents electrophilyl solution, plasma expander, glucose solution, physical saline solution, etc.
  • the core containing iron has a larger magnetic moment than iron II or iron III ions. Due to its magnetic properties, the iron-containing core enables contrasting when used as a contrast agent in MR tomography. In order to achieve an optimal contrast strength, the core should be superparamagnetic or at least contain superparamagnetic components, i. H. that the nucleus must exist as a crystal or polyatomic complex ("particle"), since this type of magnetism is only possible in solids.
  • the iron-containing core can represent or contain magnetite or maghemite.
  • the non-ferrous metal ions are paramagnetic, magnetic or a mixture of both.
  • the nanoparticles according to the invention are characterized in that the iron-containing core has a diameter, determined by electron microscopy, of less than 30 nm, preferably less than 15 nm, and contains at least 50 metal atoms and a particle size distribution, at least 90% of the iron containing nuclei are in the range 0.7 mean to 1.3 mean value.
  • the nanoparticles contain a synthetic polymer in an amount between 0.01 times and 1 times the sum of the metal ions present. An amount between 0.25 times and 0.75 times is preferred.
  • Derivatives that have been additionally substituted are used with a molecular weight of less than 100,000 Da. Substances with molecular weights that are less than 10,000 or 5000 Da are preferably used.
  • a dextran derivative or a mixture of dextran and / or dextran derivatives is particularly preferably used as the synthetic polymer.
  • the synthetic polymer can contain one or more acid groups or more functional groups in the molecule, which preferably contain N, S, P or O atoms.
  • the target and the synthesis polymer can be different or the same substances or substance mixtures, but the target polymer does not meet the conditions of Synthesis is subject to and therefore not subject to the secondary reactions of the synthetic polymer during synthesis, that is to say it is still in a physiological state.
  • the basic substance made of iron-containing core and synthetic polymer determines the physical quality of the nanoparticle, while the target polymer determines the biological behavior of the nanoparticles.
  • the target polymer is in one in the nanoparticle
  • Weight amount between 0.5 times to 50 times, preferably between 1 times to 25 times the weight of the metal ions present.
  • the nanoparticles according to the invention contain adsorption mediators, the amount of which is less than or equal to the sum of the weight of the metal ions contained.
  • the adsorption mediator increases or enables the adsorption of the target polymer onto the basic building block made of iron-containing core / synthesis polymer.
  • Peptides with the structures RRTVKHHVN, RRSRHH or also RSKRGR, or partial structures thereof, are preferably used as adsorption mediators.
  • the hydrodynamic diameter including all components of the nanoparticles is at most ten times larger than the diameter of the core containing iron and at most 20% larger than the diameter of the basic building block.
  • the nanoparticles according to the invention are composed of individual modules such as basic building block, target polymer, pharmaceutical and adsorption mediator, which can be combined at any time.
  • the preparations of the nanoparticles are low-viscosity aqueous colloidal solutions or suspensions of iron-containing stabilized particles in the nanometer range.
  • the solutions of the nanoparticles contain no larger aggregates and can be administered intravenously, so that requirements of international pharmacopoeias for parenterals with regard to particle sizes are met.
  • the basic building block can be sterilized by heat processes.
  • the process for "sterilizing" the finished nanoparticles depends on the sensitivity of the secondary coat, but aseptic production is aseptic in every case. Sterile filtration can always be carried out due to the small size of the particles.
  • the option of producing a sensitive target polymer with the sterilizable basic building block shortly before use is a further possibility of ensuring a practically sterile application solution.
  • the nanoparticles are well tolerated and have e.g. B. when used as an MR contrast medium a pronounced favorable safety distance between the diagnostic dose and the lethal dose ("margin of safety").
  • the diagnostic dose is approximately between 5 and 200 ⁇ mol (iron) per kilogram of body weight
  • the lethal dose is approximately between 20 and 50 mmol / kg body weight (measured on the rat).
  • the substances are completely biodegradable. In this way the iron-containing core is dissolved and the iron is brought into the physiological iron metabolism.
  • the molecules used as synthesis polymer or target polymer can also be metabolically converted into usable ones
  • the solutions or suspensions are colored red-brown to black, which is due to the intense color of the iron-containing crystals.
  • the distinctive Eigen ⁇ color can be used for visual detection, e.g. B. can be used as a marker substance in surgical medicine.
  • the nanoparticles are superparamagnetic or contain superparamagnetic components for detection with MR technology. The particles show physically very high saturation magnetizations, which are achieved even at low applied field strengths, and after switching off an external magnet no longer show any residual magnetization, they show no remanence.
  • the nanoparticles are formulated as solutions (suspensions) and can be applied without further preparation. Since the solutions of the nanoparticles are compatible with conventional medical solvents such as physiological sodium chloride solution, electrolyte solutions or sugar solutions, the particles can be diluted as desired and e.g. B. also be infused for special applications.
  • the production of the particulate or colloidal iron-containing cores is carried out from monomolecularly dissolved iron compounds by changing the pH and thereby causing precipitation in the presence of a stabilizer substance (synthesis polymer) after a "one-pot synthesis".
  • the synthetic polymer separates the crystal nuclei during production and thus serves to control the particle size.
  • the synthetic polymer is essential for the physical and pharmaceutical-pharmaceutical properties not only of the crystal nucleus but also of the entire nanoparticle.
  • the synthetic polymer enables a stable solution (suspension) to be obtained, since the nuclei are separated from one another to such an extent that aggregation can no longer take place (steric stabilization).
  • the solution (suspension) of iron core and residual synthetic polymer, which envelops and stabilizes the iron-containing core as the primary coat, represents the basic building block of the modular system.
  • the basic building block is characterized by its high physical and galenical quality.
  • a second essential building block is the target polymer, which is adsorbed onto the basic building block post-synthetically and surrounds the core with the primary coat with a second shell (secondary coat).
  • the secondary coat provides the top area of the nanoparticles and determines the in vivo behavior.
  • the mixture between the basic building block and the target polymer can take place at any time, so that "just in time” production is also possible.
  • the adsorption between the residual synthesis polymer and the target polymer can be improved or even made possible by an intermediate step with the addition of adsorption mediators.
  • the adsorbent can also be added in one step in a mixture with the target polymer.
  • pharmaceutical adjuvants or pharmaceuticals can be added at any time.
  • the synthesis polymer which is optimal for the physical properties can be selected without being limited by the desired biological controllability of the nanoparticles; -
  • the target polymer is not subject to the destructive conditions of the synthesis, so that many substances can be used to find the target that were previously excluded from the outset.
  • post-synthetic chemistry which in turn requires adequate reaction conditions and the integrity of the
  • Ligands impaired, applied; find it z. B. no redox reactions with disulfide-containing proteins, as in periodate oxidation with subsequent reductive amination, instead - the biological activity is retained.
  • Another important advantage is that there is no need to clean the basic building block target polymer, since no reaction solutions, such as. B. periodate, must be separated - the method is fast and therefore "just in time” nanoparticles can be produced directly before application, as it is e.g. B. with "individual" contrast media (eg autologous antibodies) is necessary or can be advantageous if the target polymer is only stable for a short time in solution.
  • reaction solutions such as. B. periodate
  • the production according to the invention also has advantages for further optimization, since here the "surface" of the nanoparticles can be modified / optimized separately and an analysis can also be carried out using modern analysis methods such as NMR spectroscopy or IR spectroscopy; Methods that cannot be used in the presence of the particular core.
  • the nanoparticles are manufactured in several stages.
  • the iron-containing core is in principle synthesized by a "one-pot synthesis", that is to say in the presence of a stabilizer substance (synthesis polymer).
  • the stable lisator substance (synthesis polymer) is dissolved in water and mixed with the monomolecular iron compounds. By increasing the pH, the iron salts are converted to the preferred oxides and precipitated.
  • the stabilizer solution can also be made alkaline and then mixed with the iron salts. The mixture is heated under reflux and then neutralized, with heating and neutralization also taking place in the reverse order.
  • the raw substance is cleaned and then the excess or not firmly adsorbed / bound synthetic polymer is adjusted to an exact weight ratio of iron to stabilizer by a desorption process.
  • This cleaned and desorbed basic substance made of core and (residual) synthetic polymer represents the basic building block of the modular nanoparticles.
  • a heat sterilization can be connected here.
  • the selected target polymer is adsorbed onto the basic building block, optionally with intermediate adsorption or co-adsorption of an adsorption mediator. Additional components such as pharmaceutical auxiliaries or pharmaceuticals can optionally be added.
  • the general manufacturing process is summarized schematically in Figure 2.
  • iron-containing cores To produce the iron-containing cores, stoichiometric amounts of iron-II and iron-III salts are mixed with one another.
  • the quality of the crystals formed is also influenced by the salts used and in general the salts of hydrochloric acid, ie the iron chlorides, are used in the literature. In principle, however, here are all salts of strong acids, e.g. B. also the sulfates or nitrates can be used. It is problematic to ensure an exact stoichiometry when using these salts, since the iron-II salts are very sensitive to oxidation. Advantages result from the use of more complex salts such as. B. the Mohr 'see salt, which is not so sensitive to oxidation.
  • organic salts is superior to the inorganic salts, since the organic anions act as a stabilizer or auxiliary stabilizer.
  • organic anions act as a stabilizer or auxiliary stabilizer.
  • B. the iron-II-gluconate, or the iron-III-citrate exposed; but other organic anions, such as. B. the fumarates, tartrates, lactates or salicylates.
  • a synthesis variant that only starts with iron (III) salt enables production without using the oxidation-sensitive iron (II) salts, and the number of "foreign ions" can be reduced.
  • This synthesis variant starts only from iron (III) salt, from which iron (II) is generated in situ by a calculated amount of reducing agent only through the reaction.
  • all reducing agents can be used which exactly reduce iron III stoichiometrically, the use of hydroxylamine is preferred since the converted hydroxylamine is converted quantitatively to laughing gas and can therefore be completely removed from the reaction mixture very easily.
  • the aim of the precipitation step is to convert iron II and iron III in a stoichiometric composition into a crystal with a defined crystal structure.
  • the formation of the corresponding oxides is achieved by increasing the pH.
  • the iron III ions [pKL Fe (OH) 3 approx. 37 *] form poorly soluble hydroxides even at a pH of approx. 2, while the iron II ions only form as hydroxides at pH 8 [pKL Fe (OH) 2 approx. 13.5] fail, it can be seen that a direct
  • organic anions can also be used as complexing agents.
  • Complex salts, organic anion salts and inorganic salts of iron II and iron III ions can also be combined with one another as desired. 22
  • iron II hydroxide and iron III hydroxide are first prepared separately. Surprisingly, the iron oxide crystals can also be produced by combining the separately prepared hydroxide solutions, heating the combined solutions accelerating the crystallization.
  • An important step in the production of the iron-containing cores is the precipitation step, in which the particulate iron compounds are formed from the low-molecular iron compounds by increasing the pH, the formation of the particles possibly taking place via the formation of colloidal iron hydroxides.
  • any substance that can increase the pH of the acidic solution of the iron salts is suitable for increasing the pH.
  • the pH increase by means of ammonia, both as a gas and as a salt, or the use of basic amines and volatile buffers is preferred.
  • the base used for the precipitation influences the overall properties in such a way that "biological" effects are also visible.
  • B Differences in the organ distribution of the particles.
  • the concentration of the basic substance should be in the range 0.1 to 10 N, preference is given here to concentrated solutions of about 1-4 N, since the formation of particles with small core sizes takes place with increasing speed of the pH increase .
  • the bases are added within 30 minutes, but preferably within 30 seconds.
  • the precipitation of the iron compounds to the particles takes place in the temperature range of 0-120 ° C, the
  • Range 50-80 ° C is preferred.
  • the basic principle is that the temperature can be low if the iron oxide is formed directly and must be high if the formation takes place via the hydroxides as an intermediate step. After the precipitation, the neutralization and then, especially when the hydroxides are present, the raw substance is heated under reflux conditions, the duration of the heating being between 0 minutes and 24 hours, preferably between 30 minutes and one hour. Neutralization and heating under reflux conditions can also be carried out in the reverse order.
  • a high intrinsic coloration is desirable for use as a contrast medium (optical marker substance) in visual detection.
  • the use as a contrast medium in magnetic resonance tomography (MRT) requires a high level of effectiveness, which is determined in this tomography method by the magnetic properties of the nanoparticles. Due to the high saturation magnetization even at low applied field strengths, such as those used in clinical MRI, the iron oxides magnite and magnetite appear to be particularly suitable when using the nanoparticles as MR contrast agents.
  • the special magnetic properties are determined here by the crystal structure of the particulate iron cores. Surprisingly, however, it is possible to incorporate foreign ions into the crystal core and still achieve the magnetite-like crystal structure. This doping with non-ferrous metal ions can in principle be done in two ways. For one, can
  • Iron II and / or iron III ions are replaced on their lattice sites by other paramagnetic metal ions and on the other hand the substitution can also be carried out with diamagnetic ions.
  • the magnetization in the magnetite crystal results only from the iron II ions, since the iron III ions occupy parallel / anti-parallel grid positions and cancel each other out in their magnetic effect.
  • An increase in the net magnetizability of the crystal can take place if ions with stronger magnetic properties than iron are used, or if the para- or diamagnetic ions do exactly the same
  • Occupation ratio on the parallel / anti-parallel lattice sites for the iron III ions is changed.
  • Gadolinium can be increased by the difference of the magnetic moment compared to the replaced iron.
  • di- and paramagnetic ions can also be incorporated together in the magnetite-like crystal lattice. The doping with the non-iron ions takes place through partial substitution of the low-molecular iron-containing starting compounds in the synthesis.
  • the general production of the iron-containing cores aims to synthesize a magnetite-like crystal lattice.
  • iron II and iron III ions are used in a ratio of 1: 1 to 1:20.
  • the synthesis is easiest if an exactly stoichiometric ratio of 1: 2 is used.
  • the ratios of iron-II to iron-III can also be obtained by reducing iron-III during synthesis by a reducing agent.
  • Iron II and / or Iron III ions can be replaced by up to 25% of the total iron (weight) by other metal ions.
  • diamagnetic ions such as lithium, magnesium or calcium, or a mixture of para- and diamagnetic ions, can also be used.
  • crystal Structure of magnetite is preferred.
  • the magnetite crystal can arise on the one hand, for. B. if the hydroxides are initially produced, or the magnetite crystal can also react further to other crystals, for. B. in the oxidation of magnetite to maghemite.
  • the special quality of the nanoparticles as a contrast medium for MRI requires superparamagnetic magnetic properties. Superparamagnetism can only occur in solids, so that another property is required that the
  • Crystals have solid-state properties, i.e. they are particulate crystals.
  • the minimum iron content must contain at least 50 iron atoms (or metal atoms) per crystal.
  • the size of the iron-containing cores can be controlled over wide ranges by variation in the synthesis (1- about 30 nm), but the synthesis of small cores with diameters smaller than 15 nm is preferred, the particle size distribution being such that at least 90% of the Particles in the range of 0.7 MW to 1.3 MW (MW equal mean diameter, determined by electron microscopy).
  • Polymers is not to be taken literally here, since both low molecular weight substances and mixtures of low molecular weight and higher molecular weight substances can be used to produce the iron-containing cores.
  • the use of low or higher molecular weight substances which contain negative charge carriers in the molecule is particularly preferred.
  • Carboxylates or analogs, phosphates (or other P-containing groups) and sulfates (or other S-containing groups) are preferred here. These derivatives can only carry a single functional group or several of the functional groups included.
  • the underlying theory assumes that the affinity for the surface of the iron-containing core is due to the interaction between the positive iron oxide surface and the negative charge in the synthetic polymer.
  • synthesis polymer contains several of the groups, the interaction is particularly pronounced ("multi-side attachment").
  • Some particularly suitable classes for stabilization during synthesis are: Low molecular weight substances, such as. B. carboxypolyalcohols, polycarboxypolyalcohols, polycarboxyalcohols, carboxyalcohols, alcohols, mono sugar, oligomeric sugars and synthetic polymers, such as. B. polyethylene glycol, polypropylene glycol and mixtures (block and copolymers), polyacrylic acid, polyvinyl alcohol, polylactic acid
  • Polylactide and polylactide glycid as well as natural or in particular partially synthetic or chemically and / or enzymatically modified natural polymers such as.
  • low molecular weight dextran derivatives which contain negative charge carriers is particularly preferred.
  • An example here is (mono-) carboxydextran; the
  • the polycarboxydextran can interact with the iron oxide surface due to the many negative charges via a "multi-side attachment".
  • the amount of synthesis polymer for stabilization during production is 0.5-20 times the weight of the sum of the metal ions contained in the batch, the total proportion in the reaction mixture being chosen so that the viscosity when polymeric synthesis polymers are used allows thorough mixing of the batch ( ⁇ 50% w / v). It is preferred to use an approximately 3-15 times excess (weight) of synthetic polymer compared to the sum of the metal ions contained.
  • Desorption can be used by using elevated temperature in combination with one of the desorption processes. Another way to influence the extent of desorption is the use of desorbing substances, such as. B. buffer solutions or surfactants.
  • a stable, physically optimal solution / suspension is obtained, which is the basic building block for the production of the specific nanoparticles.
  • the basic building blocks consist of the iron-containing core and the (residual) synthesis polymer.
  • the amount of remaining synthetic polymer is, depending on the ratio set by the desorption process, from 0.01 to 1. The range from 0.25 to 0.75 is preferred, since in this range the best compromise between stability and adsorption capacity of the basic building block results.
  • Diameter of the basic building block varies depending on the size of the iron-containing core and the synthetic polymer used and is of the order of less than 100 nm, preferably less than 50 nm. Particular preference is given to the production of basic building blocks in which the total diameter is at most five times the core diameter .
  • the basic building block is combined with a target polymer to produce the finished nanoparticle.
  • the adsorbed target polymer forms a secondary shell around the synthetic polymer / iron-containing core and forms the surface of the overall system and, in addition to the particulate character of the particles, determines the in vivo behavior.
  • the particular advantage of the manufacturing process is that practically any substance that can be adsorbed onto the basic building block can be used for the biological control of the nanoparticles.
  • the target polymers are not subject to any synthetic stress, so that even sensitive and previously unusable substances can be used as lead molecules for controlling the biological behavior.
  • Suitable target polymers are u. a. :
  • Galactoglucomannans phosphomannans, fucans, pectins, cyclodextrins, alginic acid, tragacanth and other types of gum, chitin, chitosan, agar, furcellaran, carrageenan, cellulose, celluronic acid, arabic acid and the chemically and / or enzymatically produced derivatives, which may still be can be substituted as desired and the low molecular weight degradation products of the high molecular weight compounds.
  • the polyamino and pseudopolyamino acids are also suitable.
  • Synthetic oligomers and polymers such as polyethylene glycol, polypropylene glycol, polyoxyethylene ether, polyanetholsulfonic acid, polyethylene imine, polymaleimide, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, polyvinyl pyrrolidone, polyvinyl sulfate, polyacrylic acid, polymethacrylic acid, polylactide, polylactide glycide.
  • Monomeric to oligomeric sugars and related substances such as aldo- and ketotrioses to aldo- and ketoheptoses, ketooctoses and ketononoses, anhydro sugar, monocarboxylic acids and derivatives with 5 or 6 carbon atoms in the main chain, cyclites, amino and diamino sugar, deoxy sugar, aminodeoxy sugar and aminosugar carboxylic acids, aminocyclites, phosphorus-containing derivatives of the mono- to oligomers.
  • Oligomers / polymers with anti-tumor properties such as lipopolysaccharides, ß-2, 6-fructan, ß-1, 3-glucan, manno- glucan, mannan, glucomannan, ß-1, 3/1, 6-glucane, ß-1,6-glucan, ß-1,3 / 1,4-glucan, arabinoxylan, hemicellulose, ß- 1,4-xylan, Arabinoglucan, arabinogalactan, arabinofucoglucan, ⁇ -1, 6/1, 3-glucan, ⁇ -1, 5-arabinan, ⁇ -1, 6-glucan, ß-2, 1/2, 6-fructan, ß- 2, 1-fructan.
  • lipopolysaccharides such as lipopolysaccharides, ß-2, 6-fructan, ß-1, 3-glucan, manno- glucan, mannan, glucomannan, ß-1, 3/1, 6-glucane
  • Polysaccharides can be improved by the introduction of hydrophilic and well hydrated groups.
  • substituents u. a. Methyl, ethyl, acetyl, carboxymethyl or sulfate groups can be used.
  • Surfactants and surface-active substances such as nonionic surfactants, alkyl glucosides, glucamides, alkyl maltosides, mono- and polydispersed polyoxyethylene, quaternary ammonium salts, bile acids, alkyl sulfates, betaines, CHAP derivatives.
  • Specificity also cell fragments, cells, bacterial fragments, substances from the large group of lectins, hormones and mediator substances, proteins and neoproteins, peptides and polypeptides, antibodies, antibody fragments or the "molecular recognition units” Integrins (ELAM, LECAM, VCAM etc.) or receptor-specific substances (e.g. Lewis-X, Sialyl-Lewis-X etc.).
  • It also includes the variety of blood / plasma / serum components and opsonins, the group of oligonucleotides and synthetic oligo- nucleotides, DNA and RNA or their derivatives or fragments or analogs and homologs, from the group of lipopolysaccharides, lipoproteins, glycerol esters, cholesterol and esters, or also metabolites and antimetabolites, drugs, drug conjugates, chemotherapeutics and cytostatics.
  • target polymers in addition or instead of the above.
  • examples of target polymers the chemical and / or enzymatically produced derivatives or degradation products can also be used.
  • the derivatives or the "native" target polymers can additionally carry functional groups. These functional groups can be at one end or at both ends or at any point in the underlying target molecule.
  • the functional groups can all be combined in the same or different groups. Both in the derivatives themselves and in the functional groups, those which contain N, S, 0 or P atoms, acid or analogs, hydroxyl, ether or ester groups are preferred.
  • composition of the nanoparticles depends on the respective requirement specified by the indication. Both individual and target polymers can be used
  • Target polymers e.g. B. synthetic and non-synthetic, lower and higher molecular weight, derivatized and non-derivatized, can be used.
  • the target polymer and the synthesis polymer can be the same.
  • the target polymer here is the declared synthetic polymer, but was not subject to the drastic conditions during manufacture and is therefore still in a "physiological" state.
  • the amounts of target polymer in the finished solution of the nanoparticles can be varied over a wide range. In principle, the range from 0.5 to 50 times the weight of the sum of the weight of the contained metal ions can be used, but preference is given to using amounts corresponding to 1 to about 25 times. All substances which improve or enable the adsorption between the target polymer or the mixture of the target polymers onto the surface of the iron-containing core or core plus primary coat are to be understood as adsorption mediators. In principle, the adsorption mediators must therefore have bifunctional properties, one part of the molecule containing the affinity for the basic building block, while another part of the molecule, which, however, may be identical to the first functional part, determines the affinity for the target molecule. Are suitable for. B.
  • Preferred adsorption mediators are peptides which have an affinity for the iron core or for the iron core plus primary coat. Such peptides can be selected using modern methods of biochemistry in peptide libraries. Preferred are peptides which contain the RRTVKHHVN or the RRSRHH or also RSKRGR sequence or parts thereof
  • Molecule contain [one-letter code of the amino acids s. z. B. Stryer, Biochemistry; Freeman and Comp. ; New York; 1988]
  • adsorption mediators do not have affinity required part of the molecule can also be covalently coupled to the target polymer or polymers using conventional biochemical methods, so that here the affinity for the target polymer only has to be present optionally.
  • the amount of adsorption mediator depends on the property or properties of the substances used (strength of the adsorption mediation) and on the properties of the target polymer (s); however, the maximum addition is less than or at most equal to the weight of the sum of the metal ions contained in the nucleus.
  • auxiliaries which can be contained in the solutions of the nanoparticles, can be assigned to the classes of preservatives, pH stabilizers, antioxidants, isotonic additives, peptizers and solubilizers according to their task.
  • Medically tolerable solvents such as sugar solutions, plasma expanders, electrolyte solutions, physiological saline or water ad injections, as well as parenterally administrable oily ones can be used as further auxiliaries
  • Exemplary examples of pharmaceuticals that can be contained in the solutions of the nanoparticles can be grouped into the groups antiallergics, antianaphylactics or prophylaxis, the vasodilators or vasoconstrictors, the substances that influence the blood circulation, the substances that influence the metabolism of the nanoparticles, assign the substances that influence the pharmacokinetics of the nanoparticles, the substances that change the iron balance, the substances from the field of enzyme inducers and inhibitors, or generally the mediators and antimediators.
  • Drugs from the groups of cytostatics, chemotherapy drugs, hormones and antidiabetics are of particular interest for use in therapy.
  • the pharmaceuticals can additionally be added to the solutions of the nanoparticles as an optional component or else they can be bound to the target polymers and the polymer-drug conjugate can then be used as the target polymer.
  • the "physiological" distribution behavior of the nanoparticles can be changed not only by influencing "physiological” factors such as blood circulation, lymph flow and lymph production or the like by pharmaceuticals, but the in vivo distribution can also be changed by simple physiotherapeutic measures. Particularly noteworthy here are the movements which, for. B. can be “applied” specifically by a walk or exercises on the ergometer and, in contrast, the immobility, such as. B. in bedridden patients and or use under anesthesia or the like, which leads to a completely different distribution behavior and pattern.
  • the supply of heat which can be made possible by simple use of red light or whole or partial body baths, should be mentioned in particular.
  • the supply of heat by means of a hyperthermia device, as used in many clinics for the targeted supply of heat in adjuvant tumor therapy, is particularly preferred here. Through targeted local heating, the "selectivity" can be improved through physiotherapy support.
  • the high flexibility of the modular production allows the free combination of target polymer (s), adsorption mediator (s), pharmaceutical auxiliaries and pharmaceuticals as well as the use of any composition of the nanoparticles in combination with physiotherapeutic measures.
  • the nanoparticles or the solutions can be composed of many different constituents, so that only general statements on the exact composition, which depends on the respective application, can be given:
  • Target polymer (s) 0.5 - 50
  • the total diameter of the nanoparticles including all additives is at most ten times higher (measured by a laser light scattering method, PCS) than the diameter of the core containing iron (measured by electron microscopy in a transmission arrangement; TEM).
  • PCS laser light scattering method
  • TEM transmission arrangement
  • targetability Because of their high physical quality and the particularly good controllability ("targetability") of the nanoparticles through flexible adaptation (modular structure) of the target polymer (secondary coat) to the respective question, there are many areas of use for special indications such as MR lymphography after intravenous or local interstitial administration, the tumor display, the display of functions or impaired functions, the plaque display (atherosclerosis imaging), the display of thrombi and vascular occlusions, MR angiography, perfusion examinations, the display of infarcts, the Representation of endothelial damage, the receptor imaging, the representation of the integrity of the blood-brain barrier, etc. and for differential diagnosis, in particular to differentiate between tumors / metastases and hyperplastic tissue.
  • MR lymphography after intravenous or local interstitial administration
  • the tumor display the display of functions or impaired functions
  • plaque display the display of thrombi and vascular occlusions
  • MR angiography perfusion examinations
  • infarcts the Represent
  • the nanoparticles according to the invention have a high degree of intrinsic color and, due to the combination with a target polymer, which leads to particularly high accumulation in the lymph nodes, the particles are outstandingly suitable as intraoperative marker substances for lymph node staging. With many surgical tumor removals, the lymph nodes are also removed and the pre-application of the nanoparticles makes it considerably easier for the surgeon to remove the z. To identify T. extremely small lymph nodes in the surrounding tissue.
  • the nanoparticles have a particularly wide usable time window for this indication and can be applied from approx. 60 min to more than 24 hours before the start of the operation.
  • intratumoral application or application into the tumor periphery gives the possibility, on the one hand, of staining the tumor periphery and thus increasing the delimitation of the tumor from the surrounding tissue and, on the other hand, the particles from the tumor area are disposed of via the same disposal Lymphatic vessels are removed, through which the tumor would also metastasize.
  • the nanoparticles thus show the lymph paths or lymph nodes that are particularly predestined for metastasis.
  • the particles can also be applied locally.
  • the local application can e.g. B. breast cancer can be advantageous because only a limited area is to be shown and the targeted application on the one hand high concentrations of contrast medium deposited in the target area and the other organism is not contaminated.
  • Indirect targeted application to the interstitial area of certain lymph nodes may also be necessary to confirm a diagnosis if there is an intravenous
  • nanoparticles Another area of application of the nanoparticles is their use as amplifying substances in in-vivo diagnostics based on highly sensitive measurement methods
  • the particles can be used as a drug carrier in therapy.
  • the specificity of the nanoparticles is used to transport drugs to the site of action.
  • the medicinal substances can be incorporated in the iron-containing core, adsorbed on the surface or chemically bound to the synthetic polymer and / or the target polymer.
  • An alternative is to bind the adsorption of drug-polymer conjugates or drugs to adsorption mediators.
  • a possible indication here is the accumulation of high concentrations of low molecular weight chemotherapy drugs in phagocytic cells, as is the case for B. is therapeutically necessary for many diseases with persistent microorganisms in RES cells.
  • the nanoparticle drug systems can also be selectively imaged by external magnetic fields Target area to be accumulated.
  • Target area to be accumulated.
  • small magnets for control in the target area, e.g. B. in a tumor area to implant.
  • nanoparticles as carriers for the targeted transport of medicinal substances into certain tissues
  • medicinal forms with modified active substance release can be produced.
  • the release of the active substance can be controlled by biologically cleavable drug conjugates or by storing the drug in different components of the nanoparticle with different biodegradation.
  • a Moegli ⁇ before indication is for.
  • chemotherapeutic agents and cytostatic agents come into consideration as drugs that can be specifically transported to the site of action with the nanoparticles.
  • Antimicrobial therapy also often requires the targeted transport of the drug to the site of action (e.g. tuberculosis, microorganisms persistent in macrophages).
  • Drugs for therapeutic systems in which the release takes place via the magnetic properties of the nanoparticles come along with others Antimicrobials, hormones, 'antidiabetic drugs, cytostatics and chemotherapeutics into consideration.
  • the nanoparticles can also be used as a "drug".
  • the nanoparticles in medical radiation therapy in the doping of the nanoparticles with radioactive elements, which are carried out in the core or by adsorption of suitable molecules with isotopes or molecules onto the basic building block.
  • a preferred application of the nanoparticles in radiation therapy is given, for example, in that the nanoparticles either contain a “self-emitter” via the radioactive isotope 55 Fe or in that the nanoparticles contain an isotope that is excited by an external “activation” into a steel isotope can.
  • the nucleus can contain 1- ⁇ Gd and the external excitation can be traced back to neutrons.
  • nanoparticles in radiation therapy results from the possibility of changing the nanoparticles in the core, in the synthesis or in the target polymer or in the adsorption mediator in such a way that self-emitters such as, for example, B. 123 oc j er 125- [are included.
  • the nanoparticles can also contain an isotope that is only converted into a radiating isotope by external excitation.
  • An example here is e.g. B. the labeling of the target polymer with iodine and the external excitation of the iodine K edge with monoenergetic X-rays.
  • the nanoparticles according to the invention can also be used to remove bacteria, viruses, endotoxins and exotoxins from the vasal space, on the one hand the interaction with the nanoparticles per se can lead to inactivation and on the other hand the interaction for recognizing the conjugates / adsorbates that RES can occur with subsequent intracellular inactivation.
  • Fig. 1 Schematic structure of the nanoparticles with an iron-containing core, primary coat (synthetic polymer) and secondary coat (target polymer)
  • Fig. 2 General synthetic scheme for the production of the nanoparticles according to the invention
  • Fig. 3 FTIR spectrum of mono-carboxydextran and the starting compound dextran 4
  • Fig. 4 FTIR spectrum of poly-carboxydextran and the
  • Fig. 5 MR images of rat lymph nodes embedded in agarose
  • Fig. 6 Quantitative evaluation (from Fig. 5) of the relative signal intensities for SE 2000/15 in various rat lymph nodes
  • Fig. 7 Quantitative Evaluation (from Fig. 5) of the relative signal intensities GE 135/15/15 ° in various rat lymph nodes
  • Fig. 8 Frontal pre- and post-contrast MR images of the pelvic region of the rabbit in the proton density weighted spin echo sequence (SE 2000/15)
  • Fig. 9 Frontal pre- and post-contrast MR Images of the pelvic region of the rabbit in the proton density weighted spin echo sequence (SE 2000/15).
  • Fig. 10 Relative signal intensities for SE 2000/15 in different rabbit lymph nodes 24 h p. i.
  • Fig. 11 Frontal pre- and post-contrast MR images of the pelvic region of the rabbit in the T2 * - weighted gradient echo sequence (GE 135/15/15 °)
  • Fig. 12 Frontal pre- and post-contrast MR images of the pelvic region of the rabbit in the T2 * - weighted gradient echo sequence (GE 135/15/15 °).
  • Fig. 13 Modified batch vs original substance:
  • Fig. 14 Ex vivo MR images (GE sequence) of agarose-embedded lymph nodes in the rabbit
  • Fig. 15 Relative signal intensities for GE 135/15/15 ° in various rabbit lymph nodes 24 h p. i.
  • Fig. 16 Relative signal intensities depending on the applied dose for SE 2000/15 in various rat lymph nodes 24 h after application of the nanoparticles.
  • Fig. 17 Relative signal intensities as a function of the applied dose for GE 135/15/15 ° in various rat lymph nodes after 24 hours
  • Fig. 18 Relative signal intensities for SE 2000/15 in various rat lymph nodes depending on the time after application (reference substance)
  • Fig. 19 Relative signal intensities for SE 2000/15 in various rat lymph nodes depending on the time after application of the specific nanoparticles .
  • Fig. 20 Relative signal intensities for GE 135/15/15 ° in various rat lymph nodes in
  • Fig. 21 Relative signal intensities for GE 135/15/15 ° in various rat lymph nodes depending on the time after application of the specific nanoparticles.
  • Fig. 22 Influencing lymph node accumulation through targeted application of heat.
  • Fig. 23 Transverse dynamic study of the rat abdomen with a Tl-weighted SE sequence (TR: 200 ms, TE: 10 ms) after bolus injection of the specific nanoparticles according to Example D2 (dose 20 ⁇ mol Fe / kg)
  • Fig. 24 Comparison of the relative signal intensities for SE TR / TE 200ms / l0ms in the venous vessel and the
  • Fig. 28 Demonstration of metastases in lymph nodes by visual detection in metastatic lymph nodes in the rabbit.
  • Fig. 29 Cell uptake of specific nanoparticles (with transferrin) compared to the non-specific control (nanoparticles without transferrin).
  • Fig. 30 Ex vivo MR tomographic representation of atherosclerotic plaques of the aorta of a rabbit with the modification to the nanoparticles according to example D7 (dose 200 ⁇ mol
  • Fig. 31 Histological iron detection in the atherosclerotic membrane of the rabbit aorta with Berlin blue staining.
  • Fig. 32 Histochemical detection (Berliner Blau
  • Fig. 33 Transverse Tl-weighted spin-echo dynamic study (TR: 300 ms, TE: 15 ms) of the tumor
  • Fig. 35 Time-dependent transverse proton density-weighted (SE 2000/15) recordings after application of the nanoparticles according to Example D2 (200 ⁇ mol Fe / kg).
  • A2 Synthesis of polycarboxydextran (P-C ⁇ x. 10 g of dextran T10 are weighed into a 250 ml 2-neck flask and mixed with 100 ml of 4 N NaOH. One neck of the flask is equipped with a reflux condenser and the solution is then poured on heated to about 80 ° C. While stirring (magnetic stirrer), 30 g of 6-bromohexanoic acid are added in portions through the second access, after which the access is closed by a stopper and the reaction mixture is stirred for a further 3 hours neutralization takes place with a deduction with 6 N HC1 and then a pre-concentration on a rotary evaporator (60 ° C., vacuum).
  • the unreacted reagent is separated off or the modified carboxydextrans is purified by precipitation with ethanol.
  • the white precipitate is washed, redissolved in double-distilled water and finally filtered through a 0.22 ⁇ m filter and lyophilized.
  • reaction solution is then heated under reflux conditions for about 1 hour.
  • the mixture is then heated for about 10 minutes on the open flask to drive off the unreacted ammonia.
  • the mixture is centrifuged at 2500 g for 30 min and the filtrate is evaporated to about 7 ml on a rotary evaporator, the pH is checked and, if necessary, neutralized and after the concentration has been determined using Aqua bidest. adjusted to an approximately 1 molar iron concentration and then filtered 0.22 ⁇ m.
  • the solution can be sterilized in an autoclave with pressurized steam (method A121).
  • Test animals (rat, approx. 200 g) a 50.5 cm long one filled with heparinized saline (0.2 ml) Implanted catheter and advanced about 1.5 cm to the heart. The freely movable end of the catheter was guided outside and fixed with histoacrylic. Approximately one hour after the end of the operation, the test substance is administered iv via the tail vein (approx. 1 ml / min). The blood samples were taken at different times according to the expected elimination rates of the test substances on the awake animal. After the end of the experiment, the animals were killed under ether anesthesia by bleeding from the vena cava.
  • the blood samples are centrifuged for 15 min at 2900 rpm (1000 g) and then 0.250 ml are removed from the supernatant and distilled off. Water made up to 2.0 ml and the mixture was then heated to 40 ° C.
  • the "concentration determination” is carried out by measuring the T ⁇ ; 2 ** Re l axat i ° nsze ten m t clem Relaxometer pcl20 (Bruker, Germany). The measurement was carried out with a 180 ° -90 ° IR (inversion recovery) sequence (Ti) or with a CPMG sequence (T 2 ).
  • the evaluation was carried out using a pharmacokinetic two-compartment model and the data were calculated using the pharmacokinetic computer program TOPFIT, by plotting the concentrations, expressed as reciprocal T ⁇ f 2 times (relaxation rates) minus blank values, over time .
  • TOPFIT calculates the slope of the straight line and the effect half-lives from the semi-logarithmic "concentration" time representation.
  • Example A2 poly-carboxydextran (Example A2) with a molecular weight of about 12,000 Da are bidistilled in 17.5 ml of aqua. solved.
  • the solution is degassed by blowing nitrogen.
  • 6.7 ml of 1 molar iron (III) citrate monohydrate solution are placed in a test tube and degassed with nitrogen.
  • 1.635 g of iron (II) gluconate trihydrate are added to the iron (III) solution and dissolved in the nitrogen stream.
  • the polymer solution is heated to approx. 75 ° C and the iron solution is added (under nitrogen gas).
  • the reaction mixture is mixed with about 12 ml of 3 N sodium hydroxide solution in the heat with thorough mixing within 30 seconds. Then the
  • reaction solution is then neutralized with about 6 N hydrochloric acid and heated under reflux conditions for about 1 hour. After cooling, the mixture is centrifuged at 2500 g for 30 min and the filtrate is concentrated to about 6 ml on a rotary evaporator, the pH is checked and, after the concentration has been determined, it is bidistilled with Aqua. adjusted to an approximately 1 molar iron concentration and then filtered 0.22 ⁇ m.
  • the solution can be sterilized in an autoclave
  • Example A2 poly-carboxydextran (Example A2) with a molecular weight of about 12,000 Da are bidistilled in 17.5 ml of aqua. solved. The solution is degassed by blowing nitrogen. 10 ml of 1 molar iron (III) chloride hexahydrate solution are added to the polymer solution and further degassed with nitrogen. The polymer solution is heated to approximately 75 ° C. and then 113.6 mg of hydroxylamine HCl are added (with nitrogen gas). The reaction mixture is under good heat
  • the polymer solution is heated to approx. 75 ° C and the iron solution is added (under nitrogen gas). About 11.5 ml of 3N sodium hydroxide solution are added to the reaction mixture in the heat with thorough mixing within 30 seconds. The reaction solution is then neutralized with about 6 N hydrochloric acid and heated under reflux conditions for about 1 hour. After cooling, the mixture is centrifuged at 2500 g for 30 min and the filtrate is concentrated to about 8 ml on a rotary evaporator, the pH is checked and after the concentration has been determined with Aqua bidest. to an approximately 1 molar
  • Example B1 5 ml of the solution according to Example B1 are poured into a Visking dialysis tube and dialyzed 5 times for 1 hour against 1 liter of fresh double-distilled water.
  • the retentate is adjusted to an iron concentration of 200 mmol / 1 by dilution with Aqua bidest and then filled into sterile 10 ml vials in sterile 0.22 ⁇ m filters (cellulose acetate) in portions of 5 ml.
  • the desorbed solution can be sterilized in an autoclave.
  • D3 Dextran FP1 as a lyophilisate 5.0 ml solution according to Example Cl with a concentration of 200 mmol Fe / 1 (corresponding to 56 mg total iron) are placed in a 10 ml vial.
  • 302.4 mg of dextran FP1 as Target polymer is dissolved in 6.0 ml of Aqua bidest and 5.0 ml are added to the iron oxide solution under aseptic conditions using a syringe with a filter attachment (0.22 ⁇ m).
  • the solution is lyophilized in the injection bottle and then closed.
  • the application solution is prepared by adding 10 ml of physiological saline; the
  • the bottle now contains 10 ml of 100 mmolar (iron) solution, which is suitable for intravenous MR lymphography.
  • dextran FPl as the target polymer are weighed into a 5 ml injection bottle and filled with 5.0 ml of solution according to Example Cl with a concentration of 200 mmol Fe / 1 (corresponding to 56 mg of total iron) and the bottle is then closed.
  • the dextran FP1 is released by rotating the injection bottle.
  • the preparation now contains 5 ml of 200 mmolar (iron) solution, which is directly suitable for intravenous MR lymphography.
  • the preparation now contains 10 ml of 100 mmol (iron) solution, which is suitable for use as a specific contrast agent for the display of proliferating cells (tumors).
  • Animals rat, SPF -Han Wistar; approx. 150 g
  • lymph nodes / lymph node groups An ex vivo agar phantom was used for lymph nodes / lymph node groups.
  • This ex vivo model has the advantage of being able to evaluate the accumulation in various central and peripheral lymph nodes (groups) even in small test animals (mouse, rat, rabbit) and thus also enables statements to be made on the homogeneity of the distribution; a quantification of the signal influence is possible.
  • the test animals (mouse, rat or rabbit) are injected with the solution of the nanoparticles via the tail vein (bolus). After 24 hours, the animals are sacrificed and various lymph nodes or lymph node groups are prepared (Lnn. Popliteales, Lnn. Mandibulares, Lnn. Iliacales, Lnn. Axillares, Lnn. Mandibulares, Lnn. Inguinales).
  • the lymph nodes are then poured into an agar phantom and kept in the refrigerator until the MR measurement
  • agar agar for microbiology 10 g agar agar for microbiology in 500 ml bidistilled water, the 0.5 ml Magnevist (0.5 mol / 1 gadolinium-DTPA-dimeglumine) are added for a signal-homogeneous background in the MR image are suspended. The suspension is boiled and then cooled to approx. 80 ° C. and kept at this temperature. About half of the agar solution is poured into a 0.5-1 cm thick layer in a plastic dish. After cooling, the organ samples are arranged on the agar layer (accordingly left-right half of the body or in "physiological order" from top to bottom) and fixed with a little agar solution (Pasteur pipette). Finally, a second layer of agar solution is poured over the tissue samples. The phantom is measured within 24 hours and stored in the refrigerator until examination.
  • Magnevist 0.5 mol / 1 gadolinium-DTPA-dimeglumine
  • the tissue samples are carefully removed from the agar phantom again after the MR measurement, decomposed in concentrated nitric acid and then the iron content is quantified using ICP-AES (Inductively Coupled Plasma Atomic Emission Spectroscopy).
  • ICP-AES Inductively Coupled Plasma Atomic Emission Spectroscopy
  • Fig. 5 MR images of rat lymph nodes embedded in agarose; Resection 24 h after application of the reference substance (example C2, left) or the modified substance according to example D2 (right), - dose in each case 100 ⁇ mol Fe / kg.
  • Fig. 6 Modified batch vs original substance: Quantitative evaluation (from Fig. 5) of the relative signal intensities for SE 2000/15 in various rat lymph nodes 24 h after magnetite application (100 ⁇ mol Fe / kg).
  • Fig. 7 Modified batch vs original substance: Quantitative evaluation (from Fig. 5) of the relative signal intensities GE 135/15/15 ° in various rat lymph nodes 24 h after magnetite application (100 ⁇ mol Fe / kg).
  • the lymphonodal signal reduction of mandibular, axillary, iliac, popliteal lymph nodes and the average accumulation across all lymph node groups by the batch modified with Dextran FPl as the secondary coat differs significantly (t-test, p ⁇ 0.05) from the unmodified starting compound (Fig. 6 and 7).
  • the superiority of the specific nanoparticles is already shown impressively by the optical assessment of the "blackening" of the individual lymph nodes in Figure 5. The homogeneity of the distribution across all examined lymph nodes is particularly remarkable.
  • the rabbits were pretreated about a week before the test substances were applied.
  • the test animals were given 0.5 times a sterile egg yolk suspension (oxoid) i. in the
  • Fig. 8 Frontal pre- and post-contrast MR images of the pelvic region of the rabbit in the proton density weighted spin-echo sequence (SE 2000/15). (Left: pre-contrast; right: specific substance D2 (150 ⁇ mol Fe / kg)).
  • Fig. 9 Frontal pre- and post-contrast MR images of the pelvic region of the rabbit in the proton density-weighted spin-echo sequence (SE 2000/15). (left: pre-contrast; right: starting compound C2 (150 ⁇ mol Fe / kg)).
  • Fig. 10 Specific nanoparticles vs unspecific
  • Fig. 13 Specific nanoparticles vs unspecific starting particles: Relative signal intensities for GE 135/15/15 ° in different rabbit lymph nodes
  • Fig. 14 Ex vivo MR images (GE sequence) of agarose-embedded lymph nodes in the rabbit; Dose - 150 ⁇ mol Fe / kg; left: unspecific comparison particles; right: specific nanoparticles.
  • the lymphonodal signal reduction (GE sequence) in the subiliacal, iliac and popliteal lymph nodes as well as the mean accumulation across all lymph node groups by the FPI-modified nanoparticles differs significantly (paired t-test, p ⁇ 0.05) from the unmodified ones Comparative particles (Fig. 13).
  • the more homogeneous interlymphonodal signal influence (Fig. 15) of the specific particles can also be clearly seen in the MR tomographic images of the agarose-embedded lymph nodes (Fig. 14); here, the comparison substance shows, as also observed in the rat, a strong signal reduction, but limited to the mesenteric lymph nodes.
  • Fig. 16 Specific nanoparticles according to Example D2 vs unspecific particles according to Example C2: Relative signal intensities depending on the dose applied for SE 2000/15 in various rat lymph nodes 24 h after application of the particles.
  • Fig. 17 Specific nanoparticles according to example D2 vs unspecific particles according to example C2: Relative signal intensities depending on the dose applied for GE 135/15/15 ° in various rat lymph nodes 24 h after application of the particles.
  • Tab. 11 Mean relative signal intensities and standard deviation across all lymph node stations depending on d ⁇ r. applied substance and osis.
  • Fig. 18 Comparative substance according to example C2: Relative signal intensities for SE 2000/15 in different
  • Fig. 19 Specific nanoparticles according to Example D2: Relative signal intensities for SE 2000/15 in various rat lymph nodes depending on the time after application.
  • Fig. 20 Comparative substance according to Example C2: Relative
  • Fig. 21 Specific nanoparticles according to Example D2: Relative signal intensities for GE 135/15/15 ° in different
  • rats were placed under anesthesia for 3-4 hours and then placed in a water bath for 2 hours. In this water bath, the rats lay with the left side of their body on a hot plate and with the right side of their body on an insulating plastic plate of the same height, which was not heated. This created a temperature difference between the water temperature on the left side of the body and the water temperature on the right side of the body.
  • the water temperature under the left shoulder of the rats was initially 41.0 - 41.5 ° C and after 30 minutes the temperature settled to a constant value of 41.5 - 42.0 ° C. Under the right shoulder, the water temperature was initially 37.0 - 37.5 ° C and after 30 min.
  • the constant temperature of 37.5 - 38.0 ° C was reached.
  • the nanoparticles were injected intravenously as a bolus in a dose of 100 ⁇ mol Fe / kg body weight.
  • the rats were put back in the cage and 24 h post injection the lymph nodes were prepared and examined by MRI.
  • Fig. 22 Influencing lymph node accumulation through targeted application of heat.
  • the popliteal lymph nodes can only be seen as bright spots.
  • the influence of heat treatment is impressively demonstrated in the illustration on the right.
  • the left side of the anesthetized rat lay on an insulating plastic plate and had the normal body temperature while the right side was heated in a water bath to 41.5 - 42.0 ° C.
  • the "cold" side shows practically no accumulation, while the heated side shows a high and homogeneous intralymphonodal accumulation of the nanoparticles. (Nanoparticles according to Example D 2; 100 ⁇ mol / kg body weight; 24 h pi; GE 135/15/15)
  • the rats were placed under anesthetic in the warm bath.
  • the anesthesia leads to a standstill of the peripheral muscle activity, a reduced lymph flow and a reduced vascular permeability with the result that practically no accumulation of the nanoparticles can be demonstrated without heating.
  • MR technology Device: Siemens Magnetom 1.5 T MR full body tomograph with extremity coil
  • MR parameters Siemens Magnetom 1.5 T, extremity coil, dynamic (transversal) with Tl-weighted SE sequence (TR: 200 ms, TE: 10 ms), FOV 170 mm, matrix 256x256, SD: 3 mm; - coronary MIPS of 3D flash (TR: 40 (60) ms, TE: 6 ms, FA 60 (40) °) and 3D FISP sequence (TR: 40 ms, TE: 7 ms, FA 35 °), FOV 240 mm, matrix 256x256, SD: 17 mm.
  • MR evaluation signal intensities in user-defined regions of interest of vessels (vena cava), liver, fat and muscle. The signal intensities are calculated in a standardized manner on the background.
  • Fig. 23 Transverse dynamic study of the rat abdomen with a Tl-weighted SE sequence (TR: 200 ms, TE: 10 ms) after bolus injection of the specific nanoparticles according to example D2 (dose 20 ⁇ mol Fe / kg); clear signal enhancement (1 min p.i.) in the intrahepatic vessels and the vena cava).
  • Fig. 24 Comparison of the relative signal intensities for SE TR / TE 200ms / l0ms in the venous vessel and the liver parenchyma for the specific nanoparticles according to Example D2 and the non-specific comparison substance according to Example C2; Dose 20 ⁇ mol Fe / kg, -.
  • Fig. 25 Coronary MIPS (maximum-intensity projections) from SD flash recordings (TR: 40 ms, TE: 6 ras, FA 60 °); Comparison of the specific nanoparticles according to example D2 (left) with the comparison substance C2 (right) -
  • Fig. 24 in the vena cava and liver parenchyma demonstrates the outstanding properties of the specific nanoparticles for use as contrast agents in MR angiography.
  • the enhancement is three times higher than that of the control substance and the brightening effect lasts for a long time and is very constant
  • Substance Specific Nanoparticles Animals: Rat, SPF Han-Wistar; approx. 150 g Russian rabbit (Chbb: HM, Thomae GmbH) with implanted VX2 tumor (tumor bank of the German Cancer Research Center, Heidelberg); approx.2.6 kg.
  • the tumor was implanted into the caudolateral thigh muscles by injecting 3 • 10 6 living tumor cells. The admission takes place 20 days after the implantation.
  • Rat intravenous injection of 500 ⁇ mol Fe / kg body weight
  • Rabbit Interstitial application of 20 ⁇ mol per paw Times: Rat: 1, 4 and 24 h pi Rabbit: 12 h p. i.
  • Fig. 26 Nanoparticles according to the invention as "intraoperative" marker substances for the visual detection of
  • Fig. 27 Nanoparticles according to the invention as "intraoperative" marker substances for the visual detection of lymph nodes (detailed view).
  • Fig. 28 Demonstration of metastases in lymph nodes by visual detection in metastatic lymph nodes in the rabbit. The metastases can be seen as bright recesses in the otherwise homogeneously dark colored lymph nodes.
  • the images of the rats show that a large number of different lymph node / lymph node groups can be stained by the single intravenous application of the solution of the nanoparticles.
  • the lymph nodes stand out clearly from the surrounding tissue and can be easily detected and then removed by the surgeon if necessary.
  • Transferrin as secondary coat (target polymer) substance specific nanoparticles (example D6)
  • Human myeloma cells (ATCC CRL 9068; cell line NCI H929) are at a concentration of at least 1-10 *> cells / ml in RPMI 1640 with 10% FCS and 0.05 mmol / 1
  • the cells are incubated with the nanoparticles in a concentration of 0.5 mmol / l (calculated as iron) for 18 hours.
  • the cells are pelleted, washed twice with PBS and then the cell number is determined in an aliquot (Neubauer
  • the cell pellet is concentrated in 500 ⁇ l. Nitric acid / 100 ⁇ l hydrogen peroxide dissolved by heating and made up to a volume of 5.0 ml. The iron concentration is then determined using atomic emission spectroscopy (AES, detection limit 0.1 ppm).
  • AES atomic emission spectroscopy
  • Fig. 29 Cell uptake of specific nanoparticles (with transferrin) compared to the non-specific one
  • Control nanoparticles without transferrin.
  • the NCI cells human myeloma cell line
  • the specific nanoparticles show a significantly higher uptake by the Myeloma NCI 929 cells.
  • the uptake of the nanoparticles without target polymer, which is more than 50% lower, demonstrates the advantages of the specific nanoparticles according to the invention.
  • the aorta was dissected out, carefully cut open and then rinsed with cold PBS solution in order to remove non-bound or absorbed nanoparticles. The aorta was then divided into two parts and poured into the agarose phantom and then examined by MRI.
  • Fig. 30 Ex vivo MR tomographic representation of atherosclerotic plaques of the aorta of a rabbit with the modification D7 (dose 200 ⁇ mol Fe / kg; resection of the aorta 5 h p.i.); left proton density-weighted spin-echo sequence; right T2 * weighted gradient echo sequence.
  • Fig. 31 Histological iron detection in the atherosclerotic membrane of the rabbit aorta with Berlin blue staining. The comparison with the MR tomographic image (GE 135/15/15 °) shows that the histologically proven iron adheres to the
  • Fig. 32 Histochemical detection (Berlin blue staining) of the accumulated nanoparticles according to Example D7 in the aorta of a Watanabe rabbit.
  • the upper figure shows an overview of the prepared aorta on the agar and the lower part demonstrates the good correlation of the iron staining (blue granules) with the already visually recognizable plaques in the particularly strongly modified aortic arch.
  • the MR tomographic image (“ex vivo image") of the prepared aorta shows the plaques as dark spots (signal reduction).
  • the findings from the MR scan correlate with the plaques that are already clearly visible. The largest plaques are in the area of the aortic arch and are confirmed in the MR tomographic image and the histological view; Even smaller plaques can be easily detected both in the MR image and with the histological iron staining.
  • the nanoparticles according to the invention can accumulate in tumors.
  • the studies should show that Particles represent suitable drug carriers for chemotherapeutics and, on the other hand, document that the nanoparticles can be used to check whether the therapeutics can reach their desired site of action, ie the tumor, so that here is an example of the combination of diagnosis and therapy .
  • Dosage 200 ⁇ Mol Fe / kg body weight (KGW) times: 0 - 120 minutes and 12 or 24 hours after application.
  • Fig. 33 Transversal T1-weighted spin-echo dynamic study (TR: 300 ms, TE: 15 ms) of the tumor signal behavior after bolus injection of nanoparticles according to example D2 (200 ⁇ mol Fe / kg). The images show a time-dependent slowly increasing signal enhancement in the tumor with a clearly increasing delimitation of the mass.
  • Fig. 34 Course of the relative signal intensity (accumulation) in the tumor. The temporal signal course

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2020174476A1 (en) * 2019-02-28 2020-09-03 Hadasit Medical Research Services And Development Ltd. Targeted magnetic vehicles and method of using the same

Families Citing this family (128)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4428851C2 (de) * 1994-08-04 2000-05-04 Diagnostikforschung Inst Eisen enthaltende Nanopartikel, ihre Herstellung und Anwendung in der Diagnostik und Therapie
US5855868A (en) * 1996-04-01 1999-01-05 Nycomed Imaging As Method of T1 -weighted resonance imaging of RES organs
IL128057A (en) * 1996-08-05 2001-08-26 Schering Ag Process for the production of contrast media
FR2753902B1 (fr) 1996-09-27 1999-04-02 Ioualalen Karim Nouveau type de matrice ionique biodegradable de polarite interne modulable a polymere greffe
DE19652374A1 (de) * 1996-12-04 1998-06-10 Schering Ag Verwendung von Endothelin-Konjugaten in der Therapie, neue Endothelin-Konjugate, diese enthaltende Mittel, sowie Verfahren zu deren Herstellung
WO1998037826A1 (de) * 1997-02-26 1998-09-03 Aesculap Meditec Gmbh Marker zur bestimmung seiner position in einem hohlraum innerhalb des organismus eines lebewesens
US6306166B1 (en) * 1997-08-13 2001-10-23 Scimed Life Systems, Inc. Loading and release of water-insoluble drugs
WO1999067641A2 (en) 1998-06-24 1999-12-29 Illumina, Inc. Decoding of array sensors with microspheres
US6470220B1 (en) * 1999-03-29 2002-10-22 The Regents Of The University Of California Diagnosis and treatment of cancers using in vivo magnetic domains
US7871597B2 (en) 1999-04-09 2011-01-18 Amag Pharmaceuticals, Inc. Polyol and polyether iron oxide complexes as pharmacological and/or MRI contrast agents
US6544732B1 (en) * 1999-05-20 2003-04-08 Illumina, Inc. Encoding and decoding of array sensors utilizing nanocrystals
AU4305101A (en) 1999-11-22 2001-06-04 Research Foundation Of The State University Of New York, The Magnetic nanoparticles for selective therapy
US6530944B2 (en) 2000-02-08 2003-03-11 Rice University Optically-active nanoparticles for use in therapeutic and diagnostic methods
EP1264181B1 (en) 2000-03-06 2007-06-06 Dade Behring Marburg GmbH Carriers coated with polysaccharides, their preparation and use
US7537938B2 (en) * 2000-04-28 2009-05-26 Monogram Biosciences, Inc. Biomarker detection in circulating cells
AU2001266272B2 (en) * 2000-05-03 2005-09-15 Medigene Ag Cationic diagnostic, imaging and therapeutic agents associated with activated vascular sites
US20050013775A1 (en) * 2000-06-01 2005-01-20 Kotov Nicholas A. Bioconjugates of nanoparticles as radiopharmaceuticals
US6689338B2 (en) * 2000-06-01 2004-02-10 The Board Of Regents For Oklahoma State University Bioconjugates of nanoparticles as radiopharmaceuticals
US6690962B2 (en) * 2000-09-15 2004-02-10 Institut fur Diagnostikforshung GmbH Process for graphic visualization and diagnosis of thrombi by means of nuclear spin tomography with use of particulate contrast media
CA2439381C (en) 2001-03-08 2010-10-05 Nanosolutions Gmbh Paramagnetic nanoparticles
US7081489B2 (en) * 2001-08-09 2006-07-25 Florida State University Research Foundation Polymeric encapsulation of nanoparticles
DE10154016B4 (de) * 2001-10-26 2004-02-12 Berlin Heart Ag Magnetflüssigkeit und Verfahren zur ihrer Herstellung
WO2003066066A1 (en) * 2002-02-01 2003-08-14 Vanderbilt University Targeted drug delivery methods
US20030185757A1 (en) * 2002-03-27 2003-10-02 Mayk Kresse Iron-containing nanoparticles with double coating and their use in diagnosis and therapy
US20030190475A1 (en) * 2002-04-09 2003-10-09 Everett Carpenter Magnetic nanoparticles having passivated metallic cores
US6962685B2 (en) * 2002-04-17 2005-11-08 International Business Machines Corporation Synthesis of magnetite nanoparticles and the process of forming Fe-based nanomaterials
US20040229380A1 (en) * 2002-05-21 2004-11-18 Po-Ying Chan-Hui ErbB heterodimers as biomarkers
US20040096089A1 (en) * 2002-08-16 2004-05-20 David Borsook Non-invasive functional imaging of peripheral nervous system activation in humans and animals
US20040058457A1 (en) * 2002-08-29 2004-03-25 Xueying Huang Functionalized nanoparticles
US20050064508A1 (en) * 2003-09-22 2005-03-24 Semzyme Peptide mediated synthesis of metallic and magnetic materials
US6989196B2 (en) * 2002-10-02 2006-01-24 Florida State University Research Foundation Microencapsulation of magnetic material using heat stabilization
WO2004083902A2 (en) * 2002-10-25 2004-09-30 Georgia Tech Research Corporation Multifunctional magnetic nanoparticle probes for intracellular molecular imaging and monitoring
GB0227738D0 (en) * 2002-11-28 2003-01-08 Univ Liverpool Nanoparticle conjugates and method of production thereof
AU2003900335A0 (en) * 2003-01-22 2003-02-13 Sirtex Medical Limited Microparticles for selectively targeted hyperthermia
DE10331439B3 (de) 2003-07-10 2005-02-03 Micromod Partikeltechnologie Gmbh Magnetische Nanopartikel mit verbesserten Magneteigenschaften
US7235228B2 (en) * 2003-04-15 2007-06-26 The United States Of America As Represented By The Secretary Of The Navy Fluorescent-magnetic nanoparticles with core-shell structure
WO2004097417A1 (en) * 2003-05-02 2004-11-11 Canon Kabushiki Kaisha Structured construct and producing method therefor
KR100936269B1 (ko) * 2003-06-07 2010-01-12 연세대학교 산학협력단 자성체-고분자 입자 및 그의 제조방법
US8651113B2 (en) * 2003-06-18 2014-02-18 Swr&D Inc. Magnetically responsive nanoparticle therapeutic constructs and methods of making and using
US7344491B1 (en) 2003-11-26 2008-03-18 Nanobiomagnetics, Inc. Method and apparatus for improving hearing
US7723311B2 (en) * 2003-06-18 2010-05-25 Nanobiomagnetics, Inc. Delivery of bioactive substances to target cells
WO2005002643A2 (en) * 2003-06-24 2005-01-13 Johns Hopkins University Method and products for delivering biological molecules to cells using multicomponent nanostructures
US7402398B2 (en) * 2003-07-17 2008-07-22 Monogram Biosciences, Inc. Measuring receptor homodimerization
GB0316912D0 (en) 2003-07-18 2003-08-20 Oxford Instr Superconductivity Therapeutic treatment
US20050031544A1 (en) * 2003-08-07 2005-02-10 Njemanze Philip Chidi Receptor mediated nanoscale copolymer assemblies for diagnostic imaging and therapeutic management of hyperlipidemia and infectious diseases
WO2005019470A2 (en) * 2003-08-11 2005-03-03 Monogram Biosciences, Inc. Detecting and profiling molecular complexes
DE10354361A1 (de) * 2003-11-20 2005-06-23 Eberhard-Karls-Universität Tübingen Vorrichtung zum Einbringen in mittels Kernspinresonanztomografie untersuchbares Körpergewebe
WO2005060610A2 (en) * 2003-12-11 2005-07-07 The Trustees Of Columbia University In The City Ofnew York Nano-sized particles, processes of making, compositions and uses thereof
EP1721161A4 (en) * 2004-02-11 2009-04-01 Massachusetts Inst Technology MULTIPLE-POLYMER-COATED MAGNETIC NANOCLUSTERS
US8562505B2 (en) 2004-02-20 2013-10-22 The Children's Hospital Of Philadelphia Uniform field magnetization and targeting of therapeutic formulations
US7846201B2 (en) * 2004-02-20 2010-12-07 The Children's Hospital Of Philadelphia Magnetically-driven biodegradable gene delivery nanoparticles formulated with surface-attached polycationic complex
US9028829B2 (en) * 2004-02-20 2015-05-12 The Children's Hospital Of Philadelphia Uniform field magnetization and targeting of therapeutic formulations
DE102004010387A1 (de) * 2004-03-03 2005-09-22 Siemens Ag Kontrastmittel für die Röntgen-Computertomographie
WO2005087367A1 (ja) * 2004-03-15 2005-09-22 Hitachi Maxell, Ltd. 磁性複合粒子およびその製造方法
JP2005296942A (ja) * 2004-03-15 2005-10-27 Hitachi Maxell Ltd 磁性複合粒子およびその製造方法
US7842281B2 (en) * 2004-05-10 2010-11-30 The Florida State University Research Foundation Magnetic particle composition for therapeutic hyperthermia
DE102004052533A1 (de) * 2004-10-15 2006-05-04 Mykhaylyk, Olga, Dr. Magnetische Partikel zur Verwendung in Therapie und Diagnostik
JP4999103B2 (ja) 2004-10-27 2012-08-15 セフィード 閉鎖系の多段階核酸増幅反応
US7939267B2 (en) * 2004-11-04 2011-05-10 Laboratory Corporation Of America Holdings Detection of activation of endothelial cells as surrogate marker for angiogenesis
US20060140867A1 (en) * 2004-12-28 2006-06-29 Helfer Jeffrey L Coated stent assembly and coating materials
DE102005016873A1 (de) * 2005-04-12 2006-10-19 Magforce Nanotechnologies Ag Nanopartikel-Wirstoff-Konjugate
WO2006113668A1 (en) * 2005-04-15 2006-10-26 University Of South Florida A method of transdermal drug delivery using hyaluronic acid nanoparticles
EP1721603A1 (en) * 2005-05-11 2006-11-15 Albert-Ludwigs-Universität Freiburg Nanoparticles for bioconjugation
WO2006125452A1 (en) * 2005-05-23 2006-11-30 Universite De Geneve Injectable superparamagnetic nanoparticles for treatment by hyperthermia and use for forming an hyperthermic implant
US20060281104A1 (en) * 2005-06-13 2006-12-14 Macevicz Stephen C Leuco dye particles and uses thereof
KR100806669B1 (ko) * 2005-06-23 2008-02-26 김정환 나노 입자-생체 복합체
US20100166669A1 (en) * 2005-06-28 2010-07-01 Joslin Diabetes Center, Inc. Methods of imaging inflammation in pancreatic islets
US20070009436A1 (en) * 2005-07-08 2007-01-11 Rondinone Adam J Radionuclide nanoparticles encased by inorganic shell having vector biomolecules attached thereto
EP1743530B1 (en) * 2005-07-15 2011-08-31 Unilever N.V. Iron fortified food product and additive
CZ301067B6 (cs) * 2006-02-24 2009-10-29 Ústav makromolekulární chemie AV CR Superparamagnetické nanocástice na bázi oxidu železa s modifikovaným povrchem, zpusob jejich prípravy a použití
EP2010089A4 (en) * 2006-04-21 2010-09-01 Philadelphia Children Hospital MAGNETIC GRADIENT TARGETING AND SEQUESTRATION OF THERAPEUTIC FORMULATIONS AND THERAPEUTIC SYSTEMS THEREFOR
JP5282031B2 (ja) * 2006-05-15 2013-09-04 ドミトリィ ビー カーポティン 有機物を含む磁性微粒子
KR100827292B1 (ko) * 2006-05-30 2008-05-07 애니젠 주식회사 실리콘-포함 수용성 고분자로 코팅된 나노입자 및 그의조영제로서의 용도
US8119352B2 (en) * 2006-06-20 2012-02-21 Cepheld Multi-stage amplification reactions by control of sequence replication times
US20080014285A1 (en) * 2006-07-13 2008-01-17 Di Mauro Thomas M Method of treating neurodegenerative brain disease with a composite comprising superparamagnetic nanoparticles and a therapeutic compound
US20090297626A1 (en) * 2006-11-03 2009-12-03 The Trustees Of Columbia University In The City Of New York Methods for preparing metal oxides
BRPI0721148B8 (pt) * 2006-12-18 2021-05-25 Colorobbia Italiana Spa nanopartículas magnéticas para aplicação em hipertermia, preparação destas e uso de construtos apresentando aplicação farmacológica
NZ578341A (en) 2007-01-21 2011-06-30 Hemoteq Ag Method for producing a coated catheter balloon
KR100809402B1 (ko) * 2007-01-29 2008-03-05 김정환 나노 입자 표지, 나노 입자 표지를 이용하는 진단 키트, 및진단 방법
US20080255460A1 (en) * 2007-04-13 2008-10-16 Ethicon Endo-Surgery, Inc. Nanoparticle tissue based identification and illumination
US9192697B2 (en) 2007-07-03 2015-11-24 Hemoteq Ag Balloon catheter for treating stenosis of body passages and for preventing threatening restenosis
EP2182924A1 (en) * 2007-07-26 2010-05-12 Nanoscan Imaging, Llc Methods for imaging using improved nanoparticulate contrast agents
EP2022508A1 (en) * 2007-08-07 2009-02-11 Charité-Universitätsmedizin Berlin Production of targeted MRI probes by biocompatible coupling of macromolecules with charged nanoparticles
WO2009031859A2 (en) * 2007-09-06 2009-03-12 Anygen Co., Ltd. Multi-functional complex for imaging and drug delivery
US8147803B2 (en) * 2007-11-07 2012-04-03 The University Of Houston Ultrasmall superparamagnetic iron oxide nanoparticles and uses thereof
US20090157069A1 (en) * 2007-12-06 2009-06-18 Curtis Tom Systems and methods for thermal treatment of body tissue
DE102008008522A1 (de) 2008-02-11 2009-08-13 Magforce Nanotechnologies Ag Implantierbare Nanopartikel-enthaltende Produkte
JP2009256286A (ja) * 2008-04-21 2009-11-05 Fujifilm Corp 常磁性金属化合物含有ポリマー粒子
US20100018674A1 (en) * 2008-07-22 2010-01-28 Donald John Enzinna Reservoir with moveable partition for quick recovery
WO2010102065A1 (en) 2009-03-05 2010-09-10 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
WO2010120905A2 (en) * 2009-04-15 2010-10-21 Board Of Trustees Of Michigan State University Novel nano-probes for molecular imaging and targeted therapy of diseases
US8383025B2 (en) * 2009-05-19 2013-02-26 Nanyang Technological University Method of manufacturing micro patterned device and device obtained by the method
EP2944332B1 (en) 2009-07-10 2016-08-17 Boston Scientific Scimed, Inc. Use of nanocrystals for a drug delivery balloon
WO2011008393A2 (en) * 2009-07-17 2011-01-20 Boston Scientific Scimed, Inc. Nucleation of drug delivery balloons to provide improved crystal size and density
US20110054236A1 (en) * 2009-08-25 2011-03-03 The Regents Of The University Of Michigan Compositions and methods for targeting tumors
ES2600229T3 (es) * 2009-11-12 2017-02-07 Helmholtz-Zentrum Geesthacht Zentrum für Material- und Küstenforschung GmbH Nanopartículas magnéticas biocompatibles para el tratamiento de glioblastomas
DE102009058769A1 (de) 2009-12-16 2011-06-22 MagForce Nanotechnologies AG, 10589 Temperaturabhängige Aktivierung von katalytischen Nukleinsäuren zur kontrollierten Wirkstofffreisetzung
US20110160645A1 (en) * 2009-12-31 2011-06-30 Boston Scientific Scimed, Inc. Cryo Activated Drug Delivery and Cutting Balloons
KR101057484B1 (ko) * 2010-03-19 2011-08-17 강원대학교산학협력단 소장의 조영을 위한 경구용 조영제
US8889211B2 (en) 2010-09-02 2014-11-18 Boston Scientific Scimed, Inc. Coating process for drug delivery balloons using heat-induced rewrap memory
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
US9744235B2 (en) 2010-10-19 2017-08-29 The Board Of Regents Of The University Of Oklahoma Treatment of cardiovascular disorders with targeted nanoparticles
US8740872B2 (en) 2010-10-19 2014-06-03 The Board Of Regents Of The University Of Oklahoma Magnetically-targeted treatment for cardiac disorders
US10398668B2 (en) 2010-10-19 2019-09-03 The Board Of Regents Of The University Of Oklahoma Glutamate treatment of cardiovascular disorders
KR101297815B1 (ko) 2010-11-18 2013-09-03 충남대학교산학협력단 폴리감마글루탐산과 광학영상다이의 복합체를 함유하는 센티넬 림프노드 감지용 광학영상 프로브
US8197471B1 (en) * 2011-02-14 2012-06-12 Samuel Harry Tersigni Core-excited nanoparticles and methods of their use in the diagnosis and treatment of disease
EP2675486A2 (en) 2011-02-15 2013-12-25 Semmelweis Egyetem Prussian blue based nanoparticle as multimodal imaging contrast material
KR101398214B1 (ko) * 2011-04-06 2014-05-23 주식회사 바이오리더스 음이온성 고분자와 양이온성 고분자 이온복합체 기반 고감도 자기공명영상 나노조영제 및 이의 제조방법
US9084727B2 (en) 2011-05-10 2015-07-21 Bend Research, Inc. Methods and compositions for maintaining active agents in intra-articular spaces
US8669360B2 (en) 2011-08-05 2014-03-11 Boston Scientific Scimed, Inc. Methods of converting amorphous drug substance into crystalline form
WO2013028208A1 (en) 2011-08-25 2013-02-28 Boston Scientific Scimed, Inc. Medical device with crystalline drug coating
AU2011381641B2 (en) 2011-11-21 2015-04-23 Innotherapy Inc. Hydrogel comprising catechol group-coupled chitosan or polyamine and poloxamer comprising thiol group coupled to end thereof, preparation method thereof, and hemostat using same
EP2647389A1 (en) 2012-04-04 2013-10-09 Charité - Universitätsmedizin Berlin Magnetic nanoparticle dispersion, its preparation and diagnostic and therapeutic use
US8873041B1 (en) 2013-01-29 2014-10-28 Bayspec, Inc. Raman spectroscopy using multiple excitation wavelengths
US9987616B2 (en) 2013-02-27 2018-06-05 Empire Technology Development Llc Preparation and use of magnetic polymer nanocomposites
EP2823858A1 (en) * 2013-07-12 2015-01-14 Brossel, Rémy System generating a constraint field, and medical device implementing the same
US20150064107A1 (en) * 2013-09-04 2015-03-05 King's College London Imaging agent
DE102014106603A1 (de) 2014-05-12 2015-11-12 Verein zur Förderung von Innovationen durch Forschung, Entwicklung und Technologietransfer e.V. (Verein INNOVENT e.V.) Verfahren und Vorrichtung zur Abreicherung von zirkulierenden Tumorzellen aus einer Zellsuspension
US20170342383A1 (en) 2016-05-27 2017-11-30 Corning Incorporated Lithium disilicate glass-ceramic compositions and methods thereof
US10059621B2 (en) * 2016-05-27 2018-08-28 Corning Incorporated Magnetizable glass ceramic composition and methods thereof
CN111405913A (zh) 2017-11-28 2020-07-10 康宁股份有限公司 生物活性玻璃组合物和牙本质超敏性修复
EP3717427A1 (en) 2017-11-28 2020-10-07 Corning Incorporated High liquidus viscosity bioactive glass
US10857259B2 (en) 2017-11-28 2020-12-08 Corning Incorporated Chemically strengthened bioactive glass-ceramics
CN111330023B (zh) * 2020-03-23 2023-01-31 中国科学院宁波材料技术与工程研究所慈溪生物医学工程研究所 一种磁性纳米复合材料及其制备方法与应用
DE102020116859A1 (de) 2020-06-26 2021-12-30 Pharma Development Holding Gmbh Liposomen
CN112402389A (zh) * 2020-11-24 2021-02-26 常州欧法玛制药技术有限公司 一种唑吡坦双层渗透泵控释片及其制备方法
CN112870387B (zh) * 2021-02-26 2023-08-29 中山大学孙逸仙纪念医院 一种磁性纳米药物载体及其制备方法和应用
WO2023245000A2 (en) * 2022-06-13 2023-12-21 Russell Van De Casteele Methods for processing, enrichment, delivery, formulation, uptake and testing for supplements and pharmaceuticals

Family Cites Families (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5913521B2 (ja) * 1975-06-19 1984-03-30 メイトウサンギヨウ カブシキガイシヤ 磁性酸化鉄・デキストラン複合体の製造法
US4247406A (en) * 1979-04-23 1981-01-27 Widder Kenneth J Intravascularly-administrable, magnetically-localizable biodegradable carrier
US4323056A (en) * 1980-05-19 1982-04-06 Corning Glass Works Radio frequency induced hyperthermia for tumor therapy
US4501726A (en) * 1981-11-12 1985-02-26 Schroeder Ulf Intravascularly administrable, magnetically responsive nanosphere or nanoparticle, a process for the production thereof, and the use thereof
SE8201972L (sv) * 1982-03-29 1983-09-30 Gambro Lundia Ab Magnetiskt paverkbara kristalliserade kolhydrat sferer eller partiklar att anvendas tillsammans med bioadsorberande material
US4731239A (en) * 1983-01-10 1988-03-15 Gordon Robert T Method for enhancing NMR imaging; and diagnostic use
US4735796A (en) * 1983-12-08 1988-04-05 Gordon Robert T Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease
JPS59195161A (ja) * 1983-04-21 1984-11-06 Fujirebio Inc 磁性粒子及びその製造法
US4554088A (en) * 1983-05-12 1985-11-19 Advanced Magnetics Inc. Magnetic particles for use in separations
US5720939A (en) * 1985-08-15 1998-02-24 Nycomed Imaging As Method of contrast enhanced magnetic resonance imaging using magnetically responsive-particles
US4788281A (en) * 1984-01-04 1988-11-29 Tosoni Anthony L Dextran hexonic acid derivative, ferric hydroxide complex and method manufacture thereof
GB8408127D0 (en) * 1984-03-29 1984-05-10 Nyegaard & Co As Contrast agents
JPS60260463A (ja) * 1984-06-01 1985-12-23 松下電器産業株式会社 高密度酸化物焼結体の製造方法
SE454885B (sv) * 1984-10-19 1988-06-06 Exploaterings Ab Tbf Polymerbelagda partiklar med immobiliserade metalljoner pa sin yta jemte forfarande for framstellning derav
DE3577185D1 (de) * 1984-11-01 1990-05-23 Nycomed As Paramagnetische kontrastmittel fuer die anwendung in "in vivo" nmr-diagnostischen methoden und die herstellung davon.
ATE74279T1 (de) * 1986-04-07 1992-04-15 Francois Dietlin In der tomo-densitometrie zu verwendende zusammensetzungen.
US5352432A (en) * 1986-07-03 1994-10-04 Advanced Magnetics, Inc. Hepatocyte specific composition and their use as diagnostic imaging agents
US5679323A (en) * 1986-07-03 1997-10-21 Advanced Magnetics, Inc. Hepatocyte-specific receptor-mediated endocytosis-type compositions
US4827945A (en) * 1986-07-03 1989-05-09 Advanced Magnetics, Incorporated Biologically degradable superparamagnetic materials for use in clinical applications
US5262176A (en) * 1986-07-03 1993-11-16 Advanced Magnetics, Inc. Synthesis of polysaccharide covered superparamagnetic oxide colloids
US4770183A (en) * 1986-07-03 1988-09-13 Advanced Magnetics Incorporated Biologically degradable superparamagnetic particles for use as nuclear magnetic resonance imaging agents
DE3709851A1 (de) * 1987-03-24 1988-10-06 Silica Gel Gmbh Adsorptions Te Nmr-diagnostische fluessigkeitszusammensetzungen
DE3729697A1 (de) * 1987-09-04 1989-03-23 Siemens Ag Verfahren zur herstellung von pressfaehigem granulat fuer die fertigung von oxidkeramischen produkten, insbesondere mangan-zink-ferriten
US5395688A (en) * 1987-10-26 1995-03-07 Baxter Diagnostics Inc. Magnetically responsive fluorescent polymer particles
WO1990001295A1 (en) * 1988-08-04 1990-02-22 Advanced Magnetics, Incorporated Receptor mediated endocytosis type mri contrast agents
JPH0678247B2 (ja) * 1988-10-04 1994-10-05 大塚製薬株式会社 Ｎｍｒ造影用鉄含有製剤
US5612019A (en) * 1988-12-19 1997-03-18 Gordon, Deceased; David Diagnosis and treatment of HIV viral infection using magnetic metal transferrin particles
US5393525A (en) * 1989-07-21 1995-02-28 Nycomed Imaging As Contrast medium comprising superparamagnetic or ferromagnetic particles capable of increasing viscosity after administration
JP2726520B2 (ja) * 1989-10-20 1998-03-11 名糖産業株式会社 有機磁性複合体
US5389377A (en) * 1989-12-22 1995-02-14 Molecular Bioquest, Inc. Solid care therapeutic compositions and methods for making same
US5368840A (en) * 1990-04-10 1994-11-29 Imarx Pharmaceutical Corp. Natural polymers as contrast media for magnetic resonance imaging
IL98744A0 (en) * 1990-07-06 1992-07-15 Gen Hospital Corp Method of studying biological tissue using monocrystalline particles
ATE179894T1 (de) * 1991-01-19 1999-05-15 Meito Sangyo Kk Ultrafeine magnetische metalloxideteilchen enthaltende zusammensetzung
US5370901A (en) * 1991-02-15 1994-12-06 Bracco International B.V. Compositions for increasing the image contrast in diagnostic investigations of the digestive tract of patients
DE4117782C2 (de) * 1991-05-28 1997-07-17 Diagnostikforschung Inst Nanokristalline magnetische Eisenoxid-Partikel, Verfahren zu ihrer Herstellung sowie diagnostische und/oder therapeutische Mittel
JP2939336B2 (ja) * 1991-06-11 1999-08-25 名糖産業株式会社 水溶性カルボキシ多糖−磁性酸化鉄酸化複合体
JP3189154B2 (ja) * 1991-07-18 2001-07-16 東ソー株式会社 免疫測定用担体の製造方法
JPH08500700A (ja) * 1992-06-08 1996-01-23 バイオクエスト インコーポレイテッド 分離、磁気分子スイッチ、および医療用途の無機リポソームとして使用する粒径を制御した無機粒子の製造
DE69324591T3 (de) * 1992-08-05 2004-02-12 Meito Sangyo K.K., Nagoya Verbundmaterial mit kleinem durchmesser, welches ein wasserlösliches carboxylpolysaccharid und magnetisches eisenoxid enthaltet
US5464696A (en) * 1992-08-13 1995-11-07 Bracco International B.V. Particles for NMR imaging
US5349957A (en) * 1992-12-02 1994-09-27 Sterling Winthrop Inc. Preparation and magnetic properties of very small magnetite-dextran particles
DE4301871A1 (de) * 1993-01-13 1994-07-14 Diagnostikforschung Inst Neue Mittel zur Diagnose von Gefäßerkrankungen
US5362478A (en) * 1993-03-26 1994-11-08 Vivorx Pharmaceuticals, Inc. Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell
EP0634174A1 (en) * 1993-07-13 1995-01-18 Takeda Chemical Industries, Ltd. Antianemic composition for veterinary use
US5411730A (en) * 1993-07-20 1995-05-02 Research Corporation Technologies, Inc. Magnetic microparticles
DE4428851C2 (de) * 1994-08-04 2000-05-04 Diagnostikforschung Inst Eisen enthaltende Nanopartikel, ihre Herstellung und Anwendung in der Diagnostik und Therapie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9604017A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020174476A1 (en) * 2019-02-28 2020-09-03 Hadasit Medical Research Services And Development Ltd. Targeted magnetic vehicles and method of using the same

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