WO2012001578A1 - Synthèse en une étape de nanoparticules d'oxyde de fer - Google Patents

Synthèse en une étape de nanoparticules d'oxyde de fer Download PDF

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WO2012001578A1
WO2012001578A1 PCT/IB2011/052711 IB2011052711W WO2012001578A1 WO 2012001578 A1 WO2012001578 A1 WO 2012001578A1 IB 2011052711 W IB2011052711 W IB 2011052711W WO 2012001578 A1 WO2012001578 A1 WO 2012001578A1
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iron
iii
hydroxide
oxide
hours
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PCT/IB2011/052711
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English (en)
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Dirk Burdinski
Nicole Petronella Martien Haex
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Koninklijke Philips Electronics N.V.
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Publication of WO2012001578A1 publication Critical patent/WO2012001578A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G49/00—Compounds of iron
    • C01G49/02—Oxides; Hydroxides
    • C01G49/08—Ferroso-ferric oxide [Fe3O4]
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • 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
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/22—Compounds of iron
    • C09C1/24—Oxides of iron
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/89—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by mass-spectroscopy
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/01—Particle morphology depicted by an image
    • C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer

Definitions

  • the invention relates to methods for the synthesis of iron oxide nanoparticles, the particles obtainable by these methods as well as to the use of such particles as tracer materials in Magnetic Particle Imaging (MPI) or Magnetic Particle Spectroscopy (MPS).
  • MPI Magnetic Particle Imaging
  • MPS Magnetic Particle Spectroscopy
  • Magnetic Particle Imaging is a tomographic imaging technique which relies on the nonlinearity of the magnetization curves of magnetic nanoparticles and the fact that the particle magnetization saturates at some magnetic field strength.
  • MPI uses the magnetic properties of ferromagnetic nanoparticles injected into the body to measure the spatial distribution of nanoparticles, e.g. in the blood stream. Because a body contains no naturally occurring magnetic materials visible to MPI, there is no background signal, whereas in Magnetic Resonance Imaging (MRI) approaches the thresholds for in vitro and in vivo imaging are such that the background signal from the host tissue is a crucial limiting factor.
  • MRI Magnetic Resonance Imaging
  • the MPI nanoparticles appear as bright signals in the images, from which nanoparticle concentrations can be calculated.
  • MPI can capture dynamic concentration changes as the nanoparticles change their location in the body, e.g. as they are swept along the blood stream.
  • MPS Magnetic Particle Spectroscopy
  • MPS is thus closely linked to MPI and particle properties measured by MPS are characteristic for the performance of these particles as tracers for MPI.
  • the suitability of the tracer material is intimately linked to its remagnetization properties.
  • the remagnetization of nanoparticle tracers depends on a number of parameters, most importantly on the composition of the magnetic material itself, its volume and anisotropy, and its particle size distribution. Due to toxicological considerations and experience gained from Magnetic Resonance Imaging applications, superparamagnetic particles of iron oxide (SPIOs) appear to be a suitable material for the development of MPI tracers.
  • SPIOs superparamagnetic particles of iron oxide
  • the present invention solves this problem by providing such simple and effective methods for the synthesis of iron oxide nanoparticles with a superior MPI/MPS performance.
  • the methods of the present invention comprise the following steps:
  • the method is simple, employs inexpensive starting materials and yields iron oxide nanoparticles that have a superior MPI performance in comparison to Resovist particles.
  • step (d) stirring the reaction batch in the presence of air for a defined period of time D A , after adding the base in step (b),
  • the water-soluble iron salt is selected from the group of:
  • iron(II)oxide hydroxide iron(III)oxide hydroxide or any hydrate or combination thereof.
  • the water-soluble stabilizer is selected from the group of:
  • citric acid tartaric acid, lactic acid, oxalic acid or any salt or combination thereof, or is a hydrophilic or an amphiphilic polymer such as dextran, carboxydextran, poly(ethyleneoxide-block-propyleneoxide) ("Pluronic"), poly(ethyleneoxide)-based polymer or copolymer.
  • Pluronic poly(ethyleneoxide-block-propyleneoxide)
  • the base is selected from the group of:
  • iron(III)hydroxide iron(II)iron(III)hydroxide, iron(II)oxide hydroxide, iron(III)oxide hydroxide or any hydrate or combination thereof.
  • reaction temperature T R in step (c) is selected from the group of:
  • time-period D T in step (c) is selected from the group of:
  • imaging technology such as magnetic resonance imaging, positron emission tomography, secondary photon emission spectroscopy, ultrasound imaging.
  • the present invention relates to iron oxide nanoparticles obtainable by a method described herein.
  • the present invention relates to the use of iron oxide nanoparticles obtainable by a method described herein as tracer material for Magnetic Particle Imaging (MPI) or Magnetic Particle Spectroscopy (MPS).
  • MPI Magnetic Particle Imaging
  • MPS Magnetic Particle Spectroscopy
  • Fig. 1 MP Spectra of two preparations of iron oxide nanoparticles as described in Example 1 compared to a commercial sample of Resovist (Bayer-Schering Pharma). Note that the MP signal has been normalized to the absolute iron concentration of the respective samples. The iron concentration was determined by inductively coupled plasma - atomic emission spectroscopy (ICP-AES). The difference between the MP signal of the two preparations (Examples la and lb) is small, thus indicating the good reproducibility of the synthesis method.
  • ICP-AES inductively coupled plasma - atomic emission spectroscopy
  • Fig. 2 Transmission electron microscopy images of two preparations of iron oxide nanoparticles as described in Example 1 (A: Example la, B: Example lb).
  • the average diameter of the iron oxide particle cores was determined to be 5.6 nm and 5.4 nm respectively. Considering the error margin of ⁇ 0.2 nm on these measurements, the two samples were thus not significantly different in terms of average diameter.
  • Fig. 3 MP Spectra of one preparation of iron oxide nanoparticles as described in Example 2 compared to a commercial sample of Resovist (Bayer-Schering Pharma) and the two preparations as described in Example 1. Note that the MP signal has been normalized to the intensity of the third harmonic of the spectrum, which has artificially been assigned the value 1. The iron concentration of the preparation as described in Example 2 was not determined. The difference between the MP signal of the three preparations (Examples la/ lb and 2) is not significant and falls within the sample to sample variation. DETAILED DESCRIPTION OF EMBODIMENTS
  • the present invention is directed at methods for the synthesis of iron oxide nanoparticles comprising the steps:
  • step (a) it is important to add the stabilizer (step (a)) to the reaction batch containing the iron salt before adding the base (step (b)) in order to obtain iron oxide nanoparticles with the desired properties.
  • no salts in addition to iron salt (or iron salts), stabilizer (or stabilizers) and/or base (or bases) (as designated in steps (a) and (b)) are added to the reaction batch before performing step (c), in order to increase the ionic strength of the reaction batch.
  • an iron salt or a stabilizer is considered as water-soluble if at 25 °C under atmospheric pressure in neat water, with neutral pH before the addition of the substance, a solution of that substance can be obtained that has a concentration of at least 1 nM.
  • an iron salt is defined as a salt comprising an iron ion and an organic or an inorganic counter-ion.
  • iron(II)oxide hydroxide iron(III)oxide hydroxide or any hydrate thereof.
  • combinations of water-soluble iron salts can be used, provided that the respective combination meets the requirement of water- solubility as defined herein.
  • the stabilizer has the purpose of binding to the surface of the iron oxide nanoparticle by covalent, coordinative or hydrogen bonding or by any other form of binding, thereby forming an at least partial coating on the surface.
  • the stabilizer in the context of the present invention is defined as a compound that carries at least one moiety that is capable of forming covalent, coordinative or hydrogen bonds, i.e. at least one reactive group suitable for binding to the particle surface.
  • Iron salts or hydrates thereof are not considered as stabilizers in the sense of the present invention.
  • the lower alcohols methanol, ethanol, straight chain and branched propanols and straight chain and branched butanols are not considered as stabilizers in the sense of the present invention.
  • the stabilizer contains at least two functional groups suitable for binding to the particle surface.
  • the stabilizer contains at least one anionic group that is suitable for binding to the particle surface.
  • citric acid tartaric acid, lactic acid, oxalic acid or any salt or combination thereof, or is a hydrophilic or an amphiphilic polymer such as dextran, carboxydextran,
  • Poly(ethyleneoxide-block-propyleneoxide) (“Pluronic"), poly(ethyleneoxide)-based polymer or copolymer.
  • combinations of water-soluble stabilizers can be used, provided that the respective combination meets the requirement of water-solubility as defined herein.
  • the water-soluble iron salts and stabilizers used are water-soluble in combination as well.
  • the reaction batch at the end of step (a) is a neat solution without precipitate.
  • this preferred embodiment thus defines the preferred range of concentrations used, i.e. preferred are concentrations of iron salt or iron salts and stabilizer or stabilizers that are soluble as defined herein when present in the reaction batch at the end of step (a) in combination.
  • the concentrations of the iron salt (or iron salts) and the stabilizer (or stabilizers) are equal to 1/1, 1 ⁇ 2, 1/3, 1 ⁇ 4, 1/5, 1/6, 1/7, 1/8, 1/9, 1/10, 1/20 of their saturation concentration in combination at the end of step (a).
  • the base has the purpose of lowering the pH of the reaction batch thus inducing the nucleation and growth of iron oxide nanoparticles.
  • the base in the context of the present invention should act as a Bronsted-base in aqueous solution.
  • the base should have sufficient basicity to lower the pH of the reaction batch to 10 to 13, the volume of the base that has to be added to the reaction batch present after step (a) in order to achieve this lowering of the pH should not be greater than the volume of the reaction batch before the addition of the base.
  • the base can also be an iron salt, provided that it is still a base in the sense of the invention.
  • the base can also be a stabilizer, provided that it is still a base in the sense of the invention.
  • iron(III)hydroxide iron(II)iron(III)hydroxide, iron(II)oxide hydroxide, iron(III)oxide hydroxide or any hydrate or combination thereof.
  • the pH of the reaction batch after adding of the base if measured under standard conditions at room temperature should be between 10 and 13.
  • reaction batch after adding of the base the reaction batch is exposed to a reaction temperature T R for a defined period of time D T , wherein T R > 110°C, in order to obtain the iron oxide nanoparticles.
  • T R reaction temperature
  • the sequence of steps (a), (b) and (c) is important and has to be performed in the order: first (a), then (b), finally (c).
  • reaction temperature T R in step (c) must be significantly above 100°C at 1013 mbar, i.e. step (c) must be performed under elevated pressure in a pressure-stable reaction vessel.
  • reaction temperature T R in step (c) is selected from the group of:
  • time-period D T in step (c) should be between 10 minutes and 20 hours.
  • time-period D T in step (c) is selected from the group of:
  • the methods of the invention can, further, comprise at least one of the additional steps:
  • step (d) stirring the reaction batch in the presence of air for a defined period of time D A , after adding the base in step (b),
  • the iron oxide nanoparticles obtained can further be subjected to at least one of the following:
  • imaging technology such as magnetic resonance imaging, positron emission tomography, secondary photon emission spectroscopy, ultrasound imaging.
  • step (d) of the present invention stirring the reaction batch in the presence of air after adding the base in step (b) is performed for a defined period of time D A , with D A typically ranging between 10 minutes and 2 hours.
  • the stirring of the reaction batch can be performed with a magnetic stirrer, a non-magnetic stirrer, a mechanical stirrer or without the use of a stirrer.
  • the cooling of the reaction batch to room temperature in step (e) can be performed by any suitable method.
  • the cooling is performed by natural equilibration to room temperature, i.e. without any additional means for cooling.
  • separating the iron oxide nanoparticles from the reaction batch in step (f) and purifying the iron oxide nanoparticles in step (g) can be performed by any suitable method.
  • suitable methods are known to a person of skill in the art. These methods include for example: precipitation, centrifugation, re- dissolution, dialysis.
  • the nanoparticles obtained by a method of the invention may be subjected to a treatment with oxidizing or reducing agents (step (h)).
  • oxidizing or reducing agents examples include trimethylamine-N-oxide, pyridine-N-oxide, ferrocenium hexafluorophosphate, ferrocenium tetrafluorborate.
  • the nanoparticles obtained by a method of the invention may be subjected to removal, replacement or modification of the stabilizer coated upon the surface of the particles (step(i)).
  • modifications may be carried out according to suitable chemical reactions known to a person skilled in the art, e.g. reactions as mentioned in F. Herranz et al, Chemistry - A European Journal, 2008, 14, 9126-9130; F. Herranz et al. Contrast Media & Molecular Imaging, 2008, 3, 215-222; J. Liu et al. Journal of the American Chemical Society, 2009, 131, 1354-1355; W. J. M. Mulder et al, NMR in
  • the nanoparticles obtained by a method of the invention may be subjected to clustering with or encapsulating into carriers, including micelles, liposomes, polymersomes, blood cells, polymer capsules, dendrimers, polymers, hydrogels (step (j)).
  • carriers including micelles, liposomes, polymersomes, blood cells, polymer capsules, dendrimers, polymers, hydrogels (step (j)).
  • a carrier structure comprising or composed of one or more suitable amphipathic molecules such as lipids, phospholipids, hydrocarbon-based surfactants, choloesterol, glycolipids, bile acids, saponins, fatty acids, synthetic amphipathic block copolymers or natural products like egg yolk phospholipids etc. may be used.
  • phospholipids and synthetic block copolymers are particularly preferred.
  • suitable carriers are micelles, liposomes, polymersomes, blood cells, polymer capsules, dendrimers, polymers, or hydrogels or any mixtures thereof.
  • micelle refers to a vesicle type which is also typically made of lipids, in particular phosopholipids, which are organized in a monolayer structure. Micelles typically comprise a hydrophobic interior or cavity.
  • liposome refers to a vesicle type which is typically made of lipids, in particular phospholipids, i.e. molecules forming a membrane like structure with a bilayer in aqueous environment.
  • Preferred phospholipids to be used in the context of of liposomes include phosphatidylethanolamine, phosphatidylcholine, egg
  • phosphatidylethanolamine dioleoylphosphatidylethanolamine.
  • Particularly preferred are the phospholipids MPPC, DPPC, DPPE-PEG2000 or Liss Rhod PE.
  • polymersome as used herein means a vesicle-type which is typically composed of block copolymer amphiphiles, i.e. synthetic amphiphiles that have an
  • amphiphilicity similar to that of lipids By virtue of their amphiphilic nature (having a more hydrophilic head and a more hydrophobic tail), the block copolymers are capable of self- assembly into a head-to-tail and tail-to-head bilayer structure similar to liposomes.
  • polymersomes Compared to liposomes, polymersomes have much larger molecular weights, with average molecular weights typically ranging from 1000 to 100,000, preferably of from 2500 to 50,000 and more preferably from 5000 to 25000, are typically chemically more stable, less leaky, less prone to interfere with biological membranes, and less dynamic due to a lower critical aggregation concentration. These properties result in less opsonisation and longer circulation times.
  • dendrimer as used herein means a large, synthetically produced polymer in which the atoms are arranged in an array of branches and subbranches radiating out from a central core. The synthesis and use of dendrimers is known to a person of skill in the art.
  • hydrogel as used herein means a colloidal gel in which water is the dispersion medium. Hydrogels exhibit no flow in the steady-state due to a three-dimensional crosslinked network within the gel. Hydrogels can be formed from natural or synthetic polymers. The obtainment and use of hydrogels is known to a person of skill in the art.
  • the nanoparticles obtained by a method of the invention may be subjected to decorating with targeting ligands (step (k)).
  • targeting ligand refers to a targeting entity, which allows an interaction and/or recognition of the decorated nanoparticle by compatible elements, or stabilizing or destabilizing elements, which modify the chemical, physical and/or biological properties of the nanoparticle. These elements are typically present at the outside or outer surface of the nanoparticle. Particularly preferred are elements which allow a targeting of the nanoparticle to specific tissue types, specific organs, cells or cell types or specific parts of the body, in particular the animal or human body. For example, the presence of targeting ligands may lead to a targeting of the nanoparticle to organs like liver, kidney, lungs, heart, pancreas, gall, spleen, lymphatic structures, skin, brain, muscles etc.
  • the presence of targeting ligands may lead to a targeting to specific cell types, e.g. cancerous cells which express an interacting or recognizable protein at the surface.
  • the nanoparticles may comprise proteins or peptides or fragments thereof, which offer an interaction surface at the outside of the nanoparticles.
  • protein or peptide elements are ligands which are capable of binding to receptor molecules, which are capable of interacting with ligands or other receptors, antibodies or antibody fragments or derivatives thereof, which are capable of interacting with their antigens, or avidin, streptavidin, neutravidin, lectins.
  • binding interactors like biotin, which may, for example be present in the form of biotinylated compounds like proteins or peptides etc.
  • the nanoparticle may also comprise vitamins or antigens capable of interacting with compatible integrators, e.g. vitamin binding protein or antibodies etc..
  • the nanoparticles obtained by a method of the invention may be subjected to modification with components that provide signals and/or contrast enhancement in conjunction with other imaging technology, such as magnetic resonance imaging, positron emission tomography, secondary photon emission spectroscopy, ultrasound imaging.
  • components that provide signals and/or contrast enhancement in conjunction with other imaging technology are well known in the art.
  • the present invention relates to iron oxide nanoparticles obtainable by a method according to the invention.
  • the present invention relates to the use of iron oxide nanoparticles according to the invention as tracer material for Magnetic Particle Imaging (MPI) or Magnetic Particle Spectroscopy (MPS).
  • MPI Magnetic Particle Imaging
  • MPS Magnetic Particle Spectroscopy
  • the present invention further relates to the use of iron oxide nanoparticles according to the invention as contrast agents for magnetic resonance imaging (MRI) or other medical imaging applications.
  • MRI magnetic resonance imaging
  • an iron oxide nanoparticle obtainable by a method of the invention may be employed in methods of diagnosis or treatment of a disease or pathological condition, or as an ingredient of a diagnostic or pharmaceutical composition, e.g. for the treatment or diagnosis of diseases or pathological conditions, in particular a disease, disorder, tissue or organ malfunction etc., which is targetable by nanoparticles as defined herein.
  • a pathological condition may be targetable if the diseased area or zone or the zone of malfunction is connected to the cardiovascular system.
  • a pathological condition may be targetable if the diseased area or zone or the zone of malfunction is connected to the lymphatic system.
  • a pathological condition may be targetable if the diseased area or zone or the zone of malfunction is connected to the cerebrospinal fluid system.
  • Further pathological conditions which may be targeted, i.e. may be diagnosed or treated with nanoparticles according to the present invention include, but are not limited to deficiencies or disorders of the immune system, e.g. the proliferation, differentiation, or mobilization (chemotaxis) of immune cells. Also included are deficiencies or disorders of hematopoietic cells. Examples of immunologic deficiency syndromes include blood protein disorders (e.g. agammaglobulinemia,
  • dysgammaglobulinemia ataxia telangiectasia, common variable immunodeficiency, Digeorge Syndrome, thrombocytopenia, or hemoglobinuria.
  • cardiovascular diseases, disorders, and conditions and/or cardiovascular abnormalities such as arterio-arterial fistula, arteriovenous fistula, cerebral arteriovenous malformations, congenital heart defects, pulmonary atresia, and Scimitar Syndrome.
  • Congenital heart defects include aortic
  • Cardiovascular diseases, disorders, and/or conditions also include heart disease, such as arrhythmias, carcinoid heart disease, high cardiac output, low cardiac output, cardiac tamponade, endocarditis (including bacterial), heart aneurysm, cardiac arrest, congestive heart failure, congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, heart hypertrophy, congestive cardiomyopathy, left ventricular hypertrophy, right ventricular hypertrophy, post-infarction heart rupture, ventricular septal rupture, heart valve diseases, myocardial diseases, myocardial ischemia, pericardial effusion, pericarditis (including constrictive and tuberculous), pneumopericardium, postpericardiotomy syndrome, pulmonary heart disease, rheumatic heart disease, ventricular dysfunction, hyperemia, cardiovascular pregnancy complications, Scimitar
  • Arrhythmias include sinus arrhythmia, atrial fibrillation, atrial flutter, bradycardia, extrasystole, Adams-Stokes Syndrome, bundle-branch block, sinoatrial block, long QT syndrome, parasystole, Lown-Ganong-Levine Syndrome, Mahaim type preexcitation syndrome, Wolff-Parkinson- White syndrome, sick sinus syndrome, tachycardias, and ventricular fibrillation.
  • Tachycardias include paroxysmal tachycardia, supraventricular tachycardia, accelerated idioventricular rhythm, atrioventricular nodal reentry tachycardia, ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrial nodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, and ventricular tachycardia.
  • Heart valve disease include aortic valve insufficiency, aortic valve stenosis, hear murmurs, aortic valve prolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valve insufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valve insufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspid valve insufficiency, and tricuspid valve stenosis.
  • Myocardial diseases include alcoholic cardiomyopathy, congestive v' cardiomyopathy, hypertrophic cardiomyopathy, aortic subvalvular stenosis, pulmonary subvalvular stenosis, restrictive cardiomyopathy, Chagas cardiomyopathy, endocardial fibroelastosis, endomyocardial fibrosis, Kearns Syndrome, myocardial reperfusion injury, and myocarditis.
  • Myocardial ischemias include coronary disease, such as angina pectoris, coronary aneurysm, coronary arteriosclerosis, coronary thrombosis, coronary vasospasm, myocardial infarction and myocardial stunning.
  • Cardiovascular diseases also include vascular diseases such as aneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis, Hippel-Lindau Disease, Klippel-Trenaunay- Weber Syndrome, Sturge- Weber Syndrome, angioneurotic edema, aortic diseases, Takayasu's Arteritis, aortitis, Leriche's Syndrome, arterial occlusive diseases, arteritis, enarteritis, polyarteritis nodosa, cerebrovascular diseases, disorders, and/or conditions, diabetic angiopathies, diabetic retinopathy, embolisms, thrombosis, erythromelalgia, hemorrhoids, hepatic veno-occlusive disease, hypertension, hypotension, ischemia, peripheral vascular diseases, phlebitis, pulmonary venoocclusive disease, Raynaud's disease,
  • Aneurysms include dissecting aneurysms, false aneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms, cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliac aneurysms.
  • Arterial occlusive diseases include arteriosclerosis, intermittent claudication, carotid stenosis, fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoya disease, renal artery obstruction, retinal artery occlusion, and thromboangiitis obliterans.
  • Cerebrovascular diseases, disorders, and/or conditions include carotid artery diseases, cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenous malformation, cerebral artery diseases, cerebral embolism and thrombosis, carotid artery thrombosis, sinus thrombosis, Wallenberg's syndrome, cerebral hemorrhage, epidural hematoma, subdural hematoma, subaraxhnoid hemorrhage, cerebral infarction, cerebral ischemia (including transient), subclavian steal syndrome, periventricular leukomalacia, vascular headache, cluster headache, migraine, and vertebrobasilar insufficiency.
  • autoimmune disorders such as Addison's Disease, hemolytic anemia, antiphospholipid syndrome, rheumatoid arthritis, dermatitis, allergic encephalomyelitis, glomerulonephritis, Goodpasture's-Syndrome, Graves Disease, Multiple Sclerosis, Myasthenia Gravis, Neuritis, Ophthalmia, Bullous Pemphigoid, Pemphigus, Polyendocrinopathies, Purpura, Reiter's Disease, Stiff-Man Syndrome,
  • Inflammation Guillain-Barre Syndrome, insulin dependent diabetes mellitis, or autoimmune inflammatory eye disease. Additionally included are allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems; as well as
  • hyperproliferative disorders including neoplasms, cancers or tumors, such as neoplasms, cancers or tumors located in the: abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, and urogenital tract.
  • neoplasms such as neoplasms, cancers or tumors located in the: abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, and
  • hyperproliferative disorders which may be treated are hypergammaglobulinemia, lymphoproliferative disorders, paraproteinemi as, purpura, sarcoidosis, Sezary Syndrome, Waldenstron's Macroglobulinermia, Gaucher's Disease, histiocytosis, and any other hyperproliferative disease, located in an organ system listed above.
  • neurodegenerative disease states include Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, encephalitis, demyelinating diseases, peripheral neuropathies, trauma, congenital malformations, spinal cord injuries, ischemia, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia or obsessive compulsive disorder, depression.
  • iron oxide nanoparticles obtainable by a method according to the invention may be used for transport purposes, e.g. in combination with a drug.
  • a drug may be released at a specified position within the human or animal body.
  • Iron(II) chloride tetrahydrate (0.50 g) and trisodium citrate (0.25 g) were dissolved in water (4.25 mL) and ammonium hydroxide solution (28%, 2.50 mL) was added under stirring at ambient conditions to obtain a brownish solution with a pH between 11 and 12.
  • the pressure- stable reaction vessel (50 mL volume) was sealed, heated to 134°C, and kept at this temperature for 4 hours. After cooling to room temperature, the iron oxide nanoparticles were obtained in aqueous solution.
  • the preparation was performed twice yielding two independent preparations (Example la and Example lb)
  • Iron(II) chloride tetrahydrate (0.50 g) and trisodium citrate (0.50 g) were dissolved in water (4.00 mL) and ammonium hydroxide solution (28%, 2.50 mL) was added under stirring at ambient conditions to obtain a brownish solution with a pH between 11 and 12.
  • the pressure- stable reaction vessel (50 mL volume) was sealed, heated to 134°C, and kept at this temperature for 4 hours. After cooling to room temperature, the iron oxide nanoparticles were obtained in aqueous solution.

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Abstract

L'invention concerne des procédés pour la synthèse de nanoparticules d'oxyde de fer et les particules pouvant être obtenues par ces procédés. Les particules peuvent être utilisées en tant que matériaux traceurs pour l'imagerie de particules magnétiques et pour la spectroscopie de particules magnétiques (MPS). Le procédé pour la synthèse de ces particules comprend les étapes consistant à : (i) dissoudre au moins un sel de fer hydrosoluble et au moins un stabilisant hydrosoluble dans de l'eau pour former un lot de réaction, (ii) ajouter au moins une base au lot de réaction pour obtenir un pH de 10 à 13, et (iii) exposer le lot de réaction à une température de réaction TR pendant une durée définie DT, où TR ≥ 110 °C, pour obtenir les nanoparticules d'oxyde de fer.
PCT/IB2011/052711 2010-06-29 2011-06-21 Synthèse en une étape de nanoparticules d'oxyde de fer WO2012001578A1 (fr)

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CN112326776A (zh) * 2020-10-30 2021-02-05 北京航空航天大学 P140靶向光学-磁性粒子成像细胞特异性融合装置

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105722535A (zh) * 2013-06-03 2016-06-29 美国政府卫生与公众服务部 作为磁共振成像的高性能t2造影剂的八角铁氧化物纳米颗粒
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CN112326776B (zh) * 2020-10-30 2023-10-17 北京航空航天大学 P140靶向光学-磁性粒子成像细胞特异性融合装置

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