EP1945192A2 - Particules nanometriques comme agents de contraste pour l'imagerie par resonance magnetique - Google Patents

Particules nanometriques comme agents de contraste pour l'imagerie par resonance magnetique

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Publication number
EP1945192A2
EP1945192A2 EP06806318A EP06806318A EP1945192A2 EP 1945192 A2 EP1945192 A2 EP 1945192A2 EP 06806318 A EP06806318 A EP 06806318A EP 06806318 A EP06806318 A EP 06806318A EP 1945192 A2 EP1945192 A2 EP 1945192A2
Authority
EP
European Patent Office
Prior art keywords
nanoscale particles
particles according
nanoparticles
organic complexing
gadolinium
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.)
Pending
Application number
EP06806318A
Other languages
German (de)
English (en)
Inventor
Armin Kuebelbeck
Heike Schilke
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.)
Merck Patent GmbH
Original Assignee
Merck Patent 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 Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1945192A2 publication Critical patent/EP1945192A2/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K49/1878—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 the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating
    • A61K49/1881—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 the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating wherein the coating consists of chelates, i.e. chelating group complexing a (super)(para)magnetic ion, bound to the surface
    • 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
    • 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

Definitions

  • the invention relates to nanoscale particles which consist of a core with an inert matrix, one or more covalently bound organic complexing agents in which one or more metal ions are bound with unpaired electrons and optionally one or more biomolecules covalently bound to the surface of the nuclei and a process for their preparation.
  • gadolinium Because of its optimal signaling (T1 shortening, strong paramagnetism by 7 unpaired electrons) gadolinium (Gd) is used in MRI (Magnetic Resonance Imaging or Magnetic Resonance Imaging). Due to the 7 unpaired pairs of electrons, the gadolinium induces a strong alternating electromagnetic field, which influences the spin of the neighboring water protons in such a way that their relaxation time is reduced.
  • complexing agents with very high complex formation constants are used.
  • these complexing agents are DOTA and DTPA.
  • Gd-DOTA macrocyclic gadoteric acid
  • Gadoteric acid here has a half-life of over a month.
  • the exchange of gadolinium for endogenous metal ions such as copper or zinc is well below 1%, while it can be up to 35% in other complexes.
  • Gd is literally enclosed by the organic acid DOTA and lies in the center of the chelate molecule as in a cavity, as shown by X-ray crystallographic studies.
  • the toxicity of gadolinium is thus virtually completely concealed, while its paramagnetic
  • contrast agents in MRI increases the significance of the visualization of organs. Normally, 10 to 15 ml (0.2 ml / kg
  • Body weight contrast agent injected intravenously.
  • the Gd-containing contrast agent used leads to a shortening of the relaxation time and thus to a stronger signal in the images produced.
  • contrast agents based on the transition elements manganese, iron or copper are used.
  • Paramagnetic complexes such as gadoteric acid have hydrophilic
  • Gd a contrast medium which is particularly suitable for the diagnosis of shifts in the extracellular fluid, as it occurs in tumors, edema, necrosis and ischemia.
  • Gd-DOTA The compatibility of Gd-DOTA is very good. For example, two studies involving more than 5,000 patients have shown that the rate of side effects is between 0.84% and 0.97%. Of 4,169 patients in the larger of the two studies (Caille 1991), 8 had nausea and 5 vomiting, giving a total of 0.31% for these side effects. Heat, headache, discomfort, rash, and unpleasant mouthfeel occurred in less than 0.15% of all patients. The systemic osmolality load is also negligible with gadoteric acid. The only organ that shows an increased accumulation of Gd-DOTA is the kidney, which has probably pharmacokinetic reasons. However, CDU studies with creatinine clearance below 60 ml / min showed no negative impact of Gd-DOTA on vital signs or renal function. Gd-DOTA, unlike Gd-DTPA-BMA, has not given rise to any pseudo-hypocalcaemia. The recommendation at
  • Renal Insufficiency Monitoring + take all measures to prevent renal insufficiency (hydration, dose restriction, risk / Benefit assessment). For all these reasons, gadoteric acid is approved as an MRI contrast agent not only for adults, but also for children until infancy.
  • Nanoscale gadolinium (III) -containing particles have been known for some years and have advantages over individual complexed gadolinium (III) ions, which are significant in use as contrast agents in diagnostics:
  • Zeolite GdNaY nanoparticles with very high relaxivity for application as contrast agents in magnetic resonance imaging are Gd 3+ -supported zeolite NaY nanoparticles, where gadolinium is bound only by Coloumb forces, ie not covalently the pore size of the Y zeolite is only 1.3 nm, the free proton exchange with the surrounding tissue is severely hindered.
  • WO 00/30688 (Bracco) describes substituted polycarboxylate ligand molecules and corresponding metal complexes such as Gd-DTPA and GD-DOTA derivatives as contrast agents for MRI.
  • WO 2004/009134 (Bracco) describes Gd-chelate complexes as MRI contrast agents that are trapped by the cell.
  • WO 96/09840 describes a diagnostic agent comprising a particulate material whose particles are a diagnostically effective, essentially water-insoluble crystalline material of a metal oxide (iron oxide) and a polyionic coating agent (eg chitosan, hyaluronic acid, chondroitin).
  • a metal oxide iron oxide
  • a polyionic coating agent eg chitosan, hyaluronic acid, chondroitin
  • Nanoparticles e.g., Gd chelates
  • a biocompatible coating e.g., phospholipid-polyethylene glycol
  • biomolecules such as nucleic acids, antibodies, etc.
  • WO 03/082105 Barnes Jewish Hospital describes Gd-DTPA-PE and Gd-DTPA-BOA chelate complexes surrounded by a lipid / surfactant coating.
  • Object of the present invention was to produce new contrast agents that avoid the disadvantages of the aforementioned compounds.
  • the present invention thus nanoscale particles consisting of a core with an inert matrix, one or more covalently bonded organic complexing agents in which a metal ion is bound with unpaired electrons and optionally one or more biomolecules covalently bound to the surface of the nuclei.
  • nanoscale particles consisting of a core with an inert matrix, optionally one or more, covalently bound to the surface of the nuclei biomolecules and one or more, on the surface of the nuclei via a linker covalently bonded organic complexing agent in which a metal ion is bound with unpaired electrons.
  • the core or carrier preferably consists of the inert matrix
  • silica Silica, titania, alumina or zirconia. Particularly preferred is silica.
  • the monodisperse silica particles are prepared by known processes (see EP 0216278) by the hydrolysis of tetraalkoxysilanes.
  • the average particle diameter of the monodisperse particles is 10 to 500 nm, preferably 30 to 300 nm.
  • polymers can also be used, for example. Polystyrene latexes are used.
  • nanoparticles are suspended in an ethanolic-aqueous solution and a silica ester, for example tetraethyl orthosilicate (TEOS) is added.
  • TEOS tetraethyl orthosilicate
  • the hydrolysis of the kieselesters is initiated by the addition of aqueous ammonia solution.
  • the precipitated silica preferably lies on the nanoparticles in the suspension.
  • the layer thickness can be set very accurately.
  • ultrafiltration or centrifuging at particle diameters> 50 nm the coated nanoparticles can be separated and purified.
  • metal ions are preferably paramagnetic ions from the
  • Gadolinium (III) ions are particularly preferably used.
  • organic complexing agent compounds from the group of oligo- or polycarboxylates are preferably used.
  • Diethylenetriaminepentaacetic acid (DTPA) or 1, 4,7,10-tetraazacyclodecane-1, 4,7,10-tetraacetic acid (DOTA) are particularly preferably used.
  • the metal chelate complexes are covalently linked to the surface of the support via a linker, preferably via a silane.
  • a preferred linker is 3-aminopropyltriethoxysilane (APTES).
  • APTES 3-aminopropyltriethoxysilane
  • Another object of the present invention is a process for producing nanoscale particles comprising the following
  • Process steps a) Preparation of nanoparticles, preferably of silicon dioxide, titanium dioxide, aluminum oxide and / or zirconium dioxide by wet-chemical methods b) Coating of the nanoparticles with a monomolecular layer of a halosilane. c) reaction of the nanoparticles with an azide-containing agent into azide-functionalized nanoparticles d) Preparation of one or more organic complexing agents containing one or more amines and one or more
  • Polycarboxylic acids Polycarboxylic acids, polycarboxylic acid anhydrides, polycarboxylic acid chlorides or polycarboxylic esters e) Loading of one or more complexing agents with metal ions from the group of the lanthanides f) Reaction of the azide groups functionalized nanoparticles
  • halosilane e.g. 3- (chloropropyl) triethoxysilane is used.
  • alkynamines it is possible to use all known alkynamines, preference being given to using propargylamine or 6-aminohexine (1).
  • This is reacted with a polycarboxylic acid suitable for complexing, a polycarboxylic anhydride, a polycarboxylic acid chloride or else also a polycarboxylic acid ester having a good leaving group.
  • the synthesis of a carboxylic acid amide is carried out by known methods.
  • the polycarboxylic acids DOTA and DTPA or their derivatives are reacted with a corresponding amine.
  • covalent biomolecules such as, for example, enzymes, peptides / proteins, receptor ligands or antibodies can be bound to the nanoparticles.
  • nanoparticles may be coated with dextran or polyethylene glycol to increase biocompatibility.
  • Another object of the present invention is the use of nanoscale particles as contrast agents for magnetic resonance imaging.
  • the particles according to the invention can be used as contrast agents in magnetic resonance tomography, since the superficially arranged metal ions can interact with the surrounding protons, for example from tissue fluid.
  • EP0216278 B1 by the hydrolysis of tetraalkoxysilanes in aqueous-alcoholic-ammoniacal medium, wherein initially generates a sol of primary particles and then by a continuous, controlled in accordance with the Abreagierens metered addition of tetraalkoxysilane, the resulting SiO 2 particles to the desired particle size brings.
  • the suspension obtained in the third step was treated with 0.486 g of gadolinium (III) chloride anhydrous and stirred for 8 hours at room temperature. Subsequently, the suspension was washed with deionized water with a centrifuge until chloride was no longer detectable in the wash water by means of silver nitrate solution. Thereafter, the reaction product was dried by freeze-drying.
  • gadolinium (III) chloride anhydrous
  • the dried gadolinium-loaded silica particles were dissolved in dilute hydrofluoric acid and the content of gadolinium determined by ICP-MS. 0.13% gadolinium was found in the sample.
  • a sample of the silica particles was again extensively (3x) washed with deionized water and after drying again analyzed by ICP-MS.
  • the content of gadolinium was determined to be 0.14%.
  • the slightly higher content of gadolinium can be explained by the different degrees of drying or limitations in the measuring method.
  • Crucial is that by the multiple washing of the silica particles, the content of gadolinium did not decline. That is, the gadolinium is obviously tightly covalently bound to the surface of the non-porous silica particles. The same result is also obtained in the treatment with 1 N hydrochloric acid.
  • the suspension was by means of a centrifuge at 4000 min -1 8 times with
  • silica particles functionalized in the second step with APTES were admixed with 25 ml of dimethylsulfoxide (DMSO) and the propanol-2 was distilled off on a rotary evaporator under reduced pressure.
  • DMSO dimethylsulfoxide
  • the suspension obtained in the third step was treated with 1, 0 g of gadolinium (III) chloride anhydrous and at 8 hours
  • the dried gadolinium-loaded silica particles were dissolved in dilute hydrofluoric acid and the content of gadolinium determined by ICP-MS.
  • gadolinium 0.2% gadolinium was found in the sample.
  • the higher Gd content compared to the particles produced in Example 1 can be explained by the higher surface area to volume ratio of the smaller particles. Calculated are about 1200 gadolinium ions at the
  • the nanoparticles produced in the first step are coated with a monomolecular layer of a halosilane.
  • ⁇ O ⁇ l 3- (chloropropyl) - triethoxysilane was added to the reaction mixture from the 1st step and stirred at 8O 0 C for 5h. Subsequently, the particles are centrifuged off and washed neutral with deionized water.
  • Reaction control is carried out by thin-layer chromatography.
  • the reaction mixture is taken up in 10 ml of dichloromethane, 3 times with 20 ml of 0.1 molar hydrochloric acid and extracted twice with 20 ml of ß saturated aqueous NaHCO 3. Finally, it is extracted by shaking with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
  • the dichloromethane is stripped off and the oily residue is dissolved in 4 ml of tetrahydrofuran / ethanol (1: 1 by volume).
  • To the mixture are added 1 ml of water and 0.1 g (4.4 mmol) of lithium hydroxide to cleave the ester protecting groups.
  • the hydrolysis mixture is stirred overnight and concentrated to dryness on a rotary evaporator.
  • the reaction product is taken up in 10 ml of water and 1 molar
  • the azide-functionalized nanoparticle suspension prepared in step 3 was adjusted to neutral pH using TRIS buffer.
  • the previously calculated amount of polycarboxylic monoalkynamide (from step 5) was added dropwise to the nanoparticle suspension in the presence of 50 mg of copper (I) chloride.
  • the reaction was stopped for 16 hours at room temperature.
  • the particles are centrifuged off and washed thoroughly with 0.1 molar hydrochloric acid, finally with demineralized water.
  • the gadolinium content of the particles is determined to be 0.3%

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Radiology & Medical Imaging (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Biomedical Technology (AREA)
  • Physics & Mathematics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des particules nanométriques utilisées comme agents de contraste pour l'imagerie par résonance magnétique, lesquelles particules sont constituées d'un noyau présentant une matrice inerte, d'un ou de plusieurs complexants organiques liés par liaison covalente, dans lequel ou dans lesquels un ou plusieurs ions métalliques sont liés à des électrons impairs, et, éventuellement, d'une ou de plusieurs biomolécules liées par liaison covalente à la surface des noyaux. Cette invention concerne également un procédé pour produire ces nanoparticules.
EP06806318A 2005-11-10 2006-10-17 Particules nanometriques comme agents de contraste pour l'imagerie par resonance magnetique Pending EP1945192A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005053618A DE102005053618A1 (de) 2005-11-10 2005-11-10 Nanoskalige Partikel als Kontrastmittel für die Kernspintomographie
PCT/EP2006/009982 WO2007054182A2 (fr) 2005-11-10 2006-10-17 Nanoparticules utilisees comme agents de contraste pour l'imagerie par resonance magnetique

Publications (1)

Publication Number Publication Date
EP1945192A2 true EP1945192A2 (fr) 2008-07-23

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ID=37944817

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06806318A Pending EP1945192A2 (fr) 2005-11-10 2006-10-17 Particules nanometriques comme agents de contraste pour l'imagerie par resonance magnetique

Country Status (7)

Country Link
US (1) US20080286370A1 (fr)
EP (1) EP1945192A2 (fr)
JP (1) JP2009514905A (fr)
KR (1) KR20080066999A (fr)
CN (1) CN101340900A (fr)
DE (1) DE102005053618A1 (fr)
WO (1) WO2007054182A2 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009045579A2 (fr) * 2007-06-14 2009-04-09 The Regents Of The University Of California Sondes d'imagerie multimodes pour imagerie et thérapie in vivo ciblées et non ciblées
US8147802B2 (en) * 2007-09-28 2012-04-03 General Electric Company Chelator-functionalized nanoparticles
WO2009143720A1 (fr) * 2008-05-27 2009-12-03 The Chinese University Of Hong Kong Nanoparticules, procédés de fabrication de celles-ci et marquage de cellules utilisant celles-ci
WO2010076946A1 (fr) * 2008-12-30 2010-07-08 경북대학교 산학협력단 Nanoparticules, nanoparticules complexes et leur procédé de production
EP2687234A4 (fr) 2011-03-18 2014-09-24 Konica Minolta Inc Nanoparticules de silice pour diagnostique par imagerie, procédé de fabrication de celles-ci, et agent de marquage de substance biologique
CN103007302B (zh) * 2012-12-12 2014-11-26 中国科学院宁波材料技术与工程研究所 Gd2O3-TiO2复合纳米粒子及其制备方法和应用
US10160884B2 (en) * 2015-03-23 2018-12-25 Versum Materials Us, Llc Metal compound chemically anchored colloidal particles and methods of production and use thereof
US20210379208A1 (en) * 2020-06-08 2021-12-09 Massachusetts Institute Of Technology Molecular sensors with modified ligands
CN114678179B (zh) * 2020-12-24 2025-11-14 中国科学院宁波材料技术与工程研究所 一种亲水磁性实心纳米球及其制备方法与应用
CN115869426B (zh) * 2022-12-28 2025-08-12 华润双鹤药业股份有限公司 一种钆特酸葡胺注射液及其制备方法

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DE3616133A1 (de) * 1985-09-25 1987-11-19 Merck Patent Gmbh Kugelfoermige sio(pfeil abwaerts)2(pfeil abwaerts)-partikel
RU2147243C1 (ru) * 1994-09-27 2000-04-10 Нюкомед Имагинг А/С Контрастное средство
US6342598B1 (en) * 1998-11-26 2002-01-29 Bracco International B.V. Amphipatic polycarboxylic chelates and complexes with paramagnetic metals as MRI contrast agents
EP1539249B1 (fr) * 2002-07-22 2008-07-09 Bracco Imaging S.p.A. Procedure de marquage cellulaire avec des complexes paramagnetiques en vue d'applications irm
WO2004083902A2 (fr) * 2002-10-25 2004-09-30 Georgia Tech Research Corporation Sondes nanoparticulaires magnetiques multifonctionnelles pour l'imagerie moleculaire
WO2005107818A2 (fr) * 2004-04-30 2005-11-17 University Of Florida Nanoparticules et leur utilisation dans la bioimagerie multifonctions
WO2007013877A2 (fr) * 2004-09-02 2007-02-01 The Regents Of The University Of California Conjugues peptide signal-nanocristal a semi-conducteur

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Also Published As

Publication number Publication date
WO2007054182A3 (fr) 2007-07-05
KR20080066999A (ko) 2008-07-17
WO2007054182A2 (fr) 2007-05-18
JP2009514905A (ja) 2009-04-09
DE102005053618A1 (de) 2007-05-16
US20080286370A1 (en) 2008-11-20
CN101340900A (zh) 2009-01-07

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