WO2011123030A1 - Nanoparticules comprenant un cœur d'hydroxyde d'élément terre rare amorphe et une écorce organique - Google Patents
Nanoparticules comprenant un cœur d'hydroxyde d'élément terre rare amorphe et une écorce organique Download PDFInfo
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- WO2011123030A1 WO2011123030A1 PCT/SE2011/050345 SE2011050345W WO2011123030A1 WO 2011123030 A1 WO2011123030 A1 WO 2011123030A1 SE 2011050345 W SE2011050345 W SE 2011050345W WO 2011123030 A1 WO2011123030 A1 WO 2011123030A1
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- nanoparticle
- alkyl
- independently
- rare earth
- nanoparticle according
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 113
- 238000000576 coating method Methods 0.000 title claims abstract description 61
- 239000011248 coating agent Substances 0.000 title claims abstract description 57
- 229910052761 rare earth metal Inorganic materials 0.000 title claims abstract description 28
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- 239000002244 precipitate Substances 0.000 claims description 9
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- RGAHQVPQZZNNOV-UHFFFAOYSA-N 2-diethoxyphosphorylethyl(triethoxy)silane Chemical compound CCO[Si](OCC)(OCC)CCP(=O)(OCC)OCC RGAHQVPQZZNNOV-UHFFFAOYSA-N 0.000 claims description 8
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- NIINUVYELHEORX-UHFFFAOYSA-N triethoxy(triethoxysilylmethyl)silane Chemical compound CCO[Si](OCC)(OCC)C[Si](OCC)(OCC)OCC NIINUVYELHEORX-UHFFFAOYSA-N 0.000 description 10
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- DIRSQPIRPNAECV-UHFFFAOYSA-N terbium;trihydrate Chemical compound O.O.O.[Tb] DIRSQPIRPNAECV-UHFFFAOYSA-N 0.000 description 1
- CQTBQILMJBCTRS-UHFFFAOYSA-N tetradecane-1,1-diol Chemical compound CCCCCCCCCCCCCC(O)O CQTBQILMJBCTRS-UHFFFAOYSA-N 0.000 description 1
- MYXKPFMQWULLOH-UHFFFAOYSA-M tetramethylazanium;hydroxide;pentahydrate Chemical compound O.O.O.O.O.[OH-].C[N+](C)(C)C MYXKPFMQWULLOH-UHFFFAOYSA-M 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- QUNSENANWRESNO-UHFFFAOYSA-N toluene trimethoxysilane Chemical compound CO[SiH](OC)OC.Cc1ccccc1 QUNSENANWRESNO-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- HQYALQRYBUJWDH-UHFFFAOYSA-N trimethoxy(propyl)silane Chemical compound CCC[Si](OC)(OC)OC HQYALQRYBUJWDH-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000002348 vinylic group Chemical group 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
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- 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
- A61K49/1833—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 a small organic molecule
- A61K49/1848—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 a small organic molecule the small organic molecule being a silane
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
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- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
- A61K49/0414—Particles, beads, capsules or spheres
- A61K49/0423—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
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- 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
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- A61K49/1839—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 a small organic molecule the small organic molecule being a lipid, a fatty acid having 8 or more carbon atoms in the main chain, or a phospholipid
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- 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
- A61K49/1857—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
- A61K49/186—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA the organic macromolecular compound being polyethyleneglycol [PEG]
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- 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
- Nanoparticles comprising a core of amorphous rare earth element hydroxide and an organic coating
- the present invention relates to nanoparticles as well as methods for preparing said nanoparticles as well as use of the nanoparticles as contrast agents or other uses.
- the invention specifically relates to contrast agents for visualizing or imaging biological 5 material.
- Magnetic resonance Imaging is a medical imaging modality where the soft tissues of the body are visualized by utilization of the magnetization of atomic nuclei. Normally the abundant hydrogen nuclei of the water molecules of the body are
- the strength of the MRI signal depends on the nature of the nucleus, its abundance and its local magnetic environment. These factors affect the longitudinal (Tl) and transverse (T2) relaxation times, which in turn affect the signal strength.
- Tl longitudinal
- T2 transverse
- the source of contrast in MRI is a combination of the local concentration of nuclei and their magnetic environment.
- the local magnetic environment can be modified by the presence of contrast agents and, depending on their magnetic properties, the signal can be increased (positive contrast) or decreased (negative contrast). Positive contrast agents are often preferred because interpretation of the images becomes simpler.
- gadolinium chelates Because of their small physical size ( ⁇ 1 nm) they rapidly distribute into the extracellular space (the blood plus the interstitial space between the cells of the tissues) which somewhat limits the contrast effect.
- ⁇ 1 nm the physical size of paramagnetic metal ions, such as gadolinium
- NSF Nephrogenic Systemic Fibrosis
- Bridot et al. discloses a method for production of crystalline particles of gadolinium oxide, in which larger particles than 2.2 nm have to be produced by a multistep procedure (Bridot et al. J. Am. Chem. Soc. 2007, 129, 5076).
- nanoparticles of other materials containing gadolinium ions are known, examples thereof are described in Gadolinium phosphate (H. Hifumi. S. Yamoka, A. Tanimoto, D. Citterio, K. Suzuki, J. Am. Chem. Soc. 2006, 128, 15090), gadolinium fluoride (F. Evanics, P. R. DiNonetheless, F. C. J. M van Veggel, G. J. Stanisz, R. S.
- nanoparticles of gadolinium hydroxide formed inside the hollow protein ferritin is known (Sanches, P., Dalton Trans., 2009, 800). The nanoparticles will be in rapid equilibrium with the surrounding medium and hence be unsuitable for in-vivo use in humans since it will release toxic gadolinium ions in the blood.
- the object of the present application is to provide a novel nanoparticle, methods for it preparation and use of the nanoparticle.
- the object of the present invention is achieved by a nanoparticle comprising a core of amorphous rare earth element hydroxide, and an organic coating comprising silicon atoms and phosphorus atoms.
- the object of the present invention is achieved by a composition comprising a nanoparticle comprising a core of amorphous rare earth element hydroxide, and an organic coating comprising silicon atoms and phosphorus atoms.
- the object of the present invention is achieved by using the nanoparticle or a composition comprising the nanoparticle as a contrast agent or a marker, for example as MRI contrast agent or X-ray contrast agent.
- the present invention relates to a method for obtaining nanoparticles, said method for obtaining a coated nanoparticle comprises a) providing a rare earth element salt and a hydroxide source in solution in the presence of a capping agent b) forming an intermediate nanoparticle rare earth element hydroxide; c) adding a base, one or more organo-oxysilane residue(s) according to any one of formulas I-VI, , and one or more a phosphorus containing compound (s) in the presence of a non-aqueous solvent; and d) obtaining coated rare earth element hydroxide nanoparticle, wherein the coating comprises silicon atoms and phosphorus atoms.
- Fig 1 is a schematic illustration of nanoparticles 1 according to the present invention.
- Fig 2 is a schematic illustration of nanoparticles 2 according to the present invention.
- Fig 3 is a schematic illustration of how the organo-oxysilane may be bound to the core.
- nanoparticle is used to describe a particle with a total diameter from 1- 100 nm of essentially spherical shape, i.e. excluding flakes, rods and ribbons.
- lanthanide is considered synonymous to the term “rare earth” and includes the elements La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
- transition metal includes the elements Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, Hf, Ta, W, Re, Os, Ir, Pt, Au and Hg.
- Bio-inert refers to a material that is bio-compatible, i.e. harmless to a living organism and at the same time stable to degradation in-vivo.
- “Monolayer” refers to a one molecule thick layer.
- Examples of monolayer in the present invention are fatty acid cappings and organo-oxysilanes.
- nanoparticle is conjugated the conjugate in not considered to be a part of the monolayer.
- Oriented in the context of coatings refers to a layer of coating molecules where all the heads and tails (as arbitrarily defined from case to case but as intended in the present invention we consistently refer to the silane, where present, as the head) of the coating molecules are oriented in the same way in relation to the particle core surface.
- Polydispersity is a term relating to the distribution of molecular weight in a polymeric material. Polymers are normally produced by methods that produce a variety of chain lengths with different molecular weight. They will have an average molecular weight which can be calculated in different ways. The polydispersity describes how wide the distribution is around the average molecular weight. There are mathematical ways to define a polydispersity index to quantify this property as can be found in a standard polymer chemistry textbook (J. R. Fried, Polymer Science and Technology, Prentice Hall, 1995) but for the purposes of understanding the present invention, it suffices with a qualitative picture. High polydispersity is a situation where the polymer mixture has a wide distribution of molecular weight and low polydispersity describes the opposite.
- monodisperse is normally considered synonymous to low polydispersity but it may also describe the situation where the material has been produced by a method that gives absolute control of the chain length. Typically such a material would be produced by the costly process of iterative chemical reactions and purifications. This product may also be referred to as a material of "defined molecular weight".
- TOPO is an acronym for tri-n-octylphosphine oxide
- DLS dynamic light scattering, a particle sizing method, and may also be referred to as Photon Correlation Spectroscopy or Quasi-Elastic Light Scattering.
- Hydrophilic organic residue refers to an organic residue that promote solubility in aqueous solvents and in the current invention it is implicit that they are bio-inert, which excludes polypeptides and complex carbohydrates.
- suitable hydrophilic organic residues are any group containing carbon with a molecular composition (aO+bN)/(cC+dS+eSi+fP) > 0.3 where a, b, c, d, e and f are the mol percentage of oxygen (O), nitrogen (N), carbon (C), sulfur (S), silicon (Si) and phosphorus (P), respectively.
- Capping agent refers to any surfactant as defined in any standard text on detergents (see e.g. Rosen, M.
- the capping agent becomes a removable capping, for example fatty acid capping
- Activated silane refers to a silane of the following type R n Si(X)4_ n , where X is an alkoxy group, aryloxy group, a halogen, a dialkylamino group, a nitrogen containing heterocycle or an acyloxy group.
- Oxysilane refers to any organic compounds with one or more oxygen atoms attached to the silicon atom. Non-limiting examples thereof are:
- Organicsilane refers to organic compounds containing one or more carbon silicon bonds.
- Organic -oxysilane refers to organic compounds containing one or more carbon atoms and one or more oxygen atoms attached to the silicon atom. Non-limiting examples thereof are:
- Hydrocarbon or “hydrocarbon chain” is an organic residue consisting of hydrogen and carbon.
- a hydrocarbon may, when indicated, comprise heteroatoms selected from O, S and N. This means that one or more of the carbon atoms have been replaced by a heteroatom selected from O, S or N.
- the hydrocarbon may be fully saturated or it may comprise one or more unsaturations.
- the hydrocarbon may contain any number of carbon atoms between 1 and 50.
- Alkyl refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group.
- the alkyl group may have 1 to 8 carbon atoms.
- the alkyl group of the compounds may be designated as "Ci_s alkyl" or similar designations.
- Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
- a numerical range such as “1 to 8" or “1-8” refer to each integer in the given range; e.g. , "1 to 8 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 8 carbon atoms.
- alkoxy refers to the formula -OR wherein R is a Ci_8 alkyl, e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amyloxy, iso-amyloxy and the like.
- R is a Ci_8 alkyl, e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amyloxy, iso-amyloxy and the like.
- An alkoxy may be optionally substituted.
- aryloxy refers to RO- in which R is an aryl wherein, "aryl” refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi-electron system.
- the aryl ring may be a 4-20 membered ring.
- Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
- An aryl group may be optionally substituted, e.g., phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio and the like.
- An aryloxy may be optionally substituted
- heterocycle refers to a stable 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- the heterocycle may be monocyclic, bicyclic or tricyclic.
- “Strong base” refers in the current context to bases that are stronger than hydroxide and not compatible with aqueous environments.
- “Hydrodynamic diameter” refers to the diameter of the hypothetical hard sphere that diffuses at the same speed as the particle. Hydration and shape is included in the behavior of the sphere. The term is also known as “Stokes diameter” or “Stokes- Einstein diameter.
- Conjugate refers to a molecular entity that is a fluorescence marker, dye, spin-label, radioactive marker, ligand to a biological receptor, chelate, enzyme inhibitor, enzyme substrate, antibody or anti-body related structure. See e.g. "Bioconjugate
- “Handle for conjugation” or “attachment point” refers to a bifunctional molecule that can bind to, or be incorporated in, the silane coating but leaving one reactive group that can be linked to a conjugate, as defined above.
- a typical, but not exclusive, example would be (EtO) 3 SiCH 2 CH 2 CH 2 NH 2 .
- the present invention relates to paramagnetic nanoparticles which may be used as contrast agents for visualizing or imaging biological material or for other purposes known to the skilled person, such as supporting electrolyte in capillary
- the nanoparticles comprise a particle core and coating.
- Individual particle cores consist of amorphous rare earth element hydroxide, wherein said rare earth element is a lanthanide or transition metal ion.
- the core may contain additional material.
- the particle core is paramagnetic and the metal ion is in embodiments of the invention a lanthanide (+ ⁇ ) or transition metal ion or a mixture thereof.
- at least 50 % of the rare earth elements are Y, Eu, Gd, Tb or Dy.
- the rare earth elements comprise Gd.
- at least 50 % of the rare earth elements are Gd.
- more than 95 % of the rare earth elements are Gd, such as more than 99 %.
- the lanthanide is gadolinium (+ ⁇ ). In some
- the core is amorphous.
- the core is amorphous and composed of gadolinium hydroxide.
- Gadolinium hydroxide means that minor amounts of other elements may be present as impurities.
- the core of the particle has a diameter between 1- 95 nm; such as 1-50 nm; such as 1-20 nm; such as 1-10 nm, 2-6 nm or 3-6 nm. In some embodiments,
- embodiments 2-6 nm or 3-6 nm are preferred.
- the diameter of the core is measured by TEM (transmission electron microscopy) analysis.
- the coating is organic and comprises both silicon atoms and phosphorus atoms.
- the organic coating comprises a capping agent. In some embodiments this capping agent is oleic or linoleic acid.
- the organic coating is polymeric. In some embodiments the organic coating comprises hydrophilic residues.
- the organic coating comprises one or more organosilanes. In some embodiments the organic coating is crosslinked. In some embodiments the organosilanes are crosslinked. In some embodiments the
- organosilanes are crosslinked via Si-O-Si bonds.
- organic part of the crosslinked organosilane coating is hydrophilic and bio-inert.
- the present invention relates to nanoparticles as disclosed herein for the visualization of biological material.
- the invention also relates to compositions of the nanoparticles.
- Some aspects of the invention relates to methods for preparing the nanoparticles comprising a core and a coating; and methods for preparing the core particles to be coated.
- the above mentioned nanoparticles are used to manufacture a composition for in vivo visualization or imaging of biological material or for other purposes known to the skilled person.
- the nanoparticles and compositions of said nanoparticles according to the present invention are especially suited for magnetic resonance imaging (MRI) and other imaging techniques such as X-ray, computer tomography (CT) etc.
- MRI magnetic resonance imaging
- CT computer tomography
- the invention has the advantage of being a positive contrast agent, i.e. giving a bright image. They also have advantages for dual energy CT where the favorable characteristics of the X-ray absorption spectrum of gadolinium give enhanced contrast.
- a contrast agent based on the nanoparticles of the present invention may be useful in the clinical use of MRI. It may be used to enhance the visibility of blood vessels or blood-rich tissues in general. This may be useful for diagnosing problems in the vascular system like stenoses or malformations. It may also be particularly useful for the detection of cancerous tumors since it is known that the endothelial walls of the capillaries in tumors are less organized than in healthy tissue. This allows
- nanoparticles which are too large to pass through normal vessel walls, to selectively escape into tumor tissue to give an enhanced depiction of the tumor. This effect may be further enhanced by the attachment of biomarkers on the nanoparticles, which would further increase the local concentration of nanoparticles.
- the nanoparticles may also be linked to a biomarker that labels a disease marker on the inside of blood vessels. It would be of interest with e.g. markers for angiogenesis or inflammation to light up areas with tumor growth and vulnerable atherosclerotic plaque, respectively.
- the nanoparticles is a metal ion containing core that is encapsulated in a cross-linked, bio-inert silane mesh which brings about an enhanced stability while allowing sufficient contact with the surrounding water molecules to give a good magnetic relaxivity.
- the core is amorphous.
- the metal hydroxide is gadolinium hydroxide, such as Gd(OH) 3 .
- the core is amorphous, paramagnetic Gd(OH) 3 .
- the particles have been determined to be amorphous by TEM (Transmission electron microscopy).
- Fig 1 "B” is a layer or coating of organic polymeric material most commonly composed by organo-oxysilanes that may be covalently attached to the oxide core via Gd-O-Si bonds; or via ionic binding and/or forming Gd-OH 2 -0-Si bonds (ionic binding via a hydration layer); or "B” is kept in place by non-covalent interactions or by the meshwork that is formed by the cross- linking of the organo-oxysilanes; or a combination of those binding modes.
- said organo-oxysilane layer is advantageously crosslinked to form a mesh of Si-O-Si bonds surrounding the particle core, preventing the escape of metal ions from the core.
- the organic part of the silanes is hydrophilic organic residues attached to the silanes via Si-C bonds.
- the composition of the layer (or coating) is typically a mixture of different organo-oxysilanes but the present invention also relates to the layer being composed of the same organo-oxysilane.
- the thickness of the coating is between 1 and 20 nm, or between 1 and 10 nm, or between 1 and 5 nm or preferably between 1 and 3 nm.
- the diameter of the coating is determined by the difference between the hydrodynamic diameter, determined by DLS (dynamic light scattering), and the core size as measured by TEM (transmission electron microscopy) analysis. Additionally elemental composition may be used to assist the determination. It should be emphasized that this is the contribution to the radius so the contribution to the particle diameter is twice as large.
- the thickness of the coating is between 1 and 3 nm. The coating does not necessarily have the same thickness within a particle.
- the organo-oxysilane residue has the structure O 3 S1-R 1 where the oxygens may bind to the surface of the core or to other silanes or to a hydrogen or Ci_8 alkyl group.
- R 1 may be a straight or branched hydrophilic organic residue.
- A, B, and C are independently from each other selected from the group consisting of hydrogen, Ci_8 alkyl, a bond to another silane or organo-oxysilane derivative forming an oxygen-silane bond, or is absent in which case the oxygen is directly attached to the particle core;
- n, o, p, q, r are independently from each other selected from 1-6;
- n 1-20;
- X 1 , X 2 , X 3a ' X 3b , X 4a ' X 4b , X 5a ' X 5b X 6a , X 6b , X 6c are independently from each other selected from H or Ci_s alkyl;
- Y 2 , Y 3 , Y 5 are independently from each other absent or NH;
- Y 6 is O, S, -NHCO- or -NHCONH-.
- the organo-oxysilanes according to formulas I-VI may be directly bound to the particle core, for example by one or more of A, B, and C being absent and the corresponding oxygen is attached to the particle core, for example by forming a bond to the core. Additionally the organo-oxysilanes may be bound indirectly to the core, for example by forming one or more bonds to another organo-oxysilane which is attached to the particle core.
- FIG. 3 schematically illustrates how silanes may be crosslinked at the surface of a gadolinium hydroxide particle.
- variable such as Y 2 , Y 3 and Y 5
- Y 2 , Y 3 and Y 5 are stated to be absent it means that the there is a bond.
- Y 2 , Y 3 and Y 5 are absent the methylene group in any of the compounds according to formulas II-V is bound to the carbonyl group.
- independently is used for variables it means that the variable may be selected independently other variables, for example "A, B, C are independently" means that A, B and C may be selected independently of each other.
- the organo-oxysilane is selected from branched polyethers according to Formula VI where n is selected from 1-6; each m is separately selected from 1-20 and X 6a , X 6b , X 6c are independently from each other selected from H or Ci_ 8 alkyl. In one embodiment X 6a , X 6b , X 6c are methyl. Preferred is the group of molecules where n is 3 and each m is separately from each other selected from 3, 4 or
- the coating When particles are coated with the organo-oxysilane and the obtained particles have good properties, such as good water solubility and good stability.
- the coating molecule is monodisperse and relatively low-cost to produce, as opposed to most conventionally available coating molecules.
- the coating with organo-oxysilanes results in a material which is easy to develop, for example into pharmaceutical applications since characterisation of starting materials and final product becomes easier than with conventional materials.
- the coating further comprises a phosphosilane of the general formula
- phosphosilane improves the aqueous stability.
- the coating contains a coating comprising organo-oxysilanes and a phosphosilane In some embodiments, a second silane of the formulas VIII or IX
- X 8b , X 9a , X 9b are independently from each other selected from Ci_s alkyl, acyl, aryl, or X 1 1 ; wherein X 1 1 is (Si(OX 12 )) classroomX 13 , wherein X 12 is selected from Ci_ 8 alkyl, acyl, or aryl; and X 13 is hydrogen or Ci_s alkyl,
- the second silane improves the aqueous stability
- This silane binds in between the larger organo-oxysilanes and improves the stabilizing effect of the coating without adding to the diameter of the particles.
- this is termed "hardening". It has proven that the conditions for a successful hardening must be very precise in order to obtain enhanced stability. An unsuccessful hardening results in aggregation of particles making them unsuitable for the purposes such as MRI. According to the present invention an aqueous polar solvent is used as the solvent for this procedure.
- a useful mixture is n-propanol containing 3-30 vol% or, preferably containing 10-25 vol%, and even more preferably 18-22 vol% water.
- Solvents like ethanol, 2-propanol, butanol, DMF (N,N- dimethylformamide), NMP (N-methylpyrrolidone) and other amide solvents, glymes and water miscible ethers, glycols and DMSO (dimethyl sulfoxide) can also be used.
- the heating scheme for the hardening has also proven critical in order to obtain a product having a desired balance between yield and stability.
- the hardening is performed at a scheme with 1-100 h at a temperature between 40 and 100 °C followed by 1-48 h at 100-140 °C. In one embodiment a temperature between 60 and 100 °C is kept for 24-60 h followed by 10-30 h at 1 10-130 °C. In one embodiment the first temperature is kept between 90 and 100 °C for 24-60 h.
- Suitable silanes are dimethylphosphatoethyl triethoxysilane, diethylphosphatoethyl triethoxy silane, and bis(triethoxysilyl)methane but the more easily hydro lyzed methoxy silanes only cause aggregation. Neither does a mixture of triethoxy ethyl silane and ethylphosphonic acid diethyl ester work so it is important that there are two functionalities in the same molecule for the hardening to be efficient.
- the coating contains a coating comprising organo-oxysilanes and a phosphosilane and is hardened with a second silane as described above.
- the nanoparticle has an elemental composition of 10-30 weight% of gadolinium, 2-10 weight% of silicon, 1-8 weight% of phosphorus, and 20-50 weight% of carbon of the total weight of the nanoparticle. Residual ash after burning at red heat is preferably 30-60 weight%.
- layer B (Fig 1 and Fig 2) is made entirely of an organic, crosslinked polymer preventing the escape of metal ions by the mesh formed by the polymer. Many possible polymers can be envisioned for this purpose some, but not limiting, are based on amides or vinylic groups or aromatic groups or any combination of the above.
- a typical composition would be polystyrene cross-linked by divinyl benzene which is then further derivatized with polar chains to enhance bio-inertness and aqueous stability.
- Polymer networks based on polyacrylamide, polyalcohols or polyethers may also be contemplated.
- the nanoparticle comprises attachment points for introduction of at least one conjugate. In some embodiments, more than one conjugate is present and in some embodiments combinations of conjugates are present.
- the nanoparticle comprising attachment points for introduction of at least one conjugate may be formed by the treatment of the nanoparticle according to the present invention in a second step, in which a nanoparticle as visualized in Fig 2 is formed. Most attachment points are introduced by an attachment group, which is a third silane according to the following formula
- organic or inorganic residues are Ci_s alkyl, Ci_s alkenyl, Ci_s alkynyl, Ci_s alkynyl, Ci_s alkylidene; Ci_s alkoxy, thiols (Z is SH) and a maleimido group.
- each R is independently from each other selected from Ci_s alkyl, acyl, aryl, or di-Ci_s alkylamino;
- X 10 is selected from (CH 2 ) n - (OCH 2 CH 2 ) m -, where n is 1-6 and m is 0-50;
- the attachment points are introduced in the form of a primary amino group.
- the attachment point is introduced by the treatment with 3-aminopropyltriethoxysilane.
- other functional groups can be utilized.
- the attachment point may be introduced together with the organo-oxysilane; with the phosphosilane, with the second silane or after the hardening.
- the nanoparticle comprises a particle core and coating wherein the coating is obtained by addition of organo-oxysilanes and by performing cross- linking and/or hardening by treatment with a phosphosilane; a disilane; a polysilane; and/or a molecule containing any combination of phosphonates and silanes. Where appropriate, hardening may be carried out thereafter.
- a conjugate is included in the nanoparticle. In one embodiment the conjugate is at least one biomarker
- the composition may advantageously be lower in gadolinium and correspondingly higher, typically between 5 and 30 mol % of the total metal content, in the luminescent elements europium or terbium. As produced, these particles are not luminescent due to the presence of energy dissipating OH groups but the materials can be heated in a second step to produce luminescent particles.
- the present invention refers to a method for preparation of a nanoparticle according to the present invention. In one particular aspect, the present invention refers to a method for preparation of the nanoparticle according to fig 1 as disclosed above.
- One embodiment relates to a method for obtaining a coated nanoparticle according comprising: providing a rare earth element salt and a hydroxide source in solution in the presence of a capping agent; forming an intermediate nanoparticle rare earth element hydroxide; adding a base, one or more organo-oxysilane residue(s) , and one or more a phosphorus containing compound (s), in the presence of a non-aqueous solvent; and obtaining coated rare earth element hydroxide nanoparticle.
- the method may be performed by combining the step.
- the method for preparation of a nanoparticle comprises the following main steps of production of particle cores, coating the particle cores with organo-oxysilanes and performing cross-linking and/or hardening by treatment with a phosphosilane; a disilane; a polysilane; and/or a molecule containing any
- a conjugate is added to the particle.
- the conjugate is at least one biomarker.
- detergent capped precursor particles are produced.
- the particle cores are capped by a stabilizing but removable layer of capping agent.
- An example of a capping agent is oleate.
- the first step is based on the formation of a metal hydroxide by reaction of a metal salt with a source of hydroxide ions.
- a specific example is the formation of gadolinium hydroxide by the reaction of gadolinium chloride with tetramethyl ammonium hydroxide in an ethanol solution in the presence of capping agent(s) as described in example 1.
- the particle size (including the oleate capping, as measured by DLS in cyclohexane) can be tuned from 5 to 20 nm. More base generally give larger particles. This method is very convenient because it directly yields isolatable particles with the correct core size in a tunable way.
- the gadolinium chloride is a convenient source of gadolinium ions but any of the common salts like gadolinium bromide, gadolinium nitrate, gadolinium acetate or gadolinium acetoacetate etc may be used. Gadolinium chloride may also be generated in situ by the action of hydrochloric acid on gadolinium oxide or gadolinium metal.
- the source of hydroxide ions is tetramethyl ammonium hydroxide but other sources of hydroxide ions soluble in the medium can be contemplated for this purpose.
- the solvent may be ethanol, another alcohol, THF (tetrahydrofuran) or any polar organic solvent.
- the most convenient capping agent is oleic acid but most low melting fatty acids or other anionic detergents, either alone or in a mixture would be obvious variations to one skilled in the art.
- the particles turned out to be less polydisperse in the presence of oleyl alcohol, oleyl amine or 1,2-tetradecanediol. This is surprising since analysis of the finished particles show no trace of oleyl alcohol. It was found to be advantageous for the re-suspendability of the particles to add a small amount of trioctyl phosphine oxide to the particle solution before freeze drying. Typically 1-10% (w/w) was sufficient and most commonly 4 % was used.
- the capped nanoparticles may be oleate capped nanoparticles.
- the capping is oleic acid and/or oleyl alcohol and thus oleate capped nanoparticles are produced and optionally isolated. It is contemplated that any capping agent may be used any capped nanoparticles are produced.
- the produced capped nanoparticle cores for example oleate capped nanoparticles, are considered intermediate nanoparticles.
- the capped nanoparticle cores may be isolated and purified. Addition of an equal volume of acetone selectively precipitates impurities in the form of larger particle aggregates.
- a strong base such as KOt-Bu (Potassium tert- butoxide) or LiHMDS (Lithium bis(trimethylsilyl)amide) or sodium hydride or an alkyl lithium or an organomagnesium compound or a metal amide such as LDA (lithium diisopropylamide)
- a non-aqueous polar solvent such as THF
- trimethoxy silane instead of the more common (and less sensitive) triethoxy silanes to displace the capping agent and form an oriented organo-oxysilane layer (example 2).
- the oleate capped precursor particles are freely soluble in non-polar solvents like cyclohexane and toluene. After the polar coating has been bound to the particles, the material is insoluble in non-polar solvents but soluble in water, DMF and/or THF.
- the coated particles can be purified by dissolution in THF and precipitated by diethyl ether or another non- solvent, where unreacted coating precursors are soluble but the coated particles are not.
- cross-linking/hardening of the organosilane by treatment with a phosphonate-silane, a disilane, or a mixture of the two is achieved.
- treatment of the particles from step 2 with e. g. organo-oxysilane 2 with e. g. organo-oxysilane 2 in aqueous propanol at 95 °C for 48 h and then 120 °C for 24 h in a sealed ampoule affected this in an efficient manner, without causing the aggregation of the particles. Aggregation is a problem under most other conditions. It seems that very few compounds are efficient in this step. It works well with dimethylphosphatoethyl triethoxysilane,
- diethylphosphatoethyl triethoxy silane and bis(trietoxysilyl)methane but the more easily hydro lyzed methoxy silanes only cause aggregation.
- a mixture of triethoxy ethyl silane and ethylphosphonic acid diethyl ester work so it is important that there are two functionalities in the same molecule for the hardening to be efficient.
- the hardened coated nanoparticles may be further treated in order to introduce one or more functional groups allowing attachment of at least one conjugate. Handles for conjugation (attachment points) may be introduced.
- the functional groups are introduced in the form of a primary amino group by the treatment with 3-aminopropyltriethoxysilane.
- Conjugates may be selected from biomarkers, fluorescence markers, dyes, spin-labels, radioactive markers, metal chelators, antenna chromophores, ligands to a biological receptor, enzyme inhibitors, enzyme substrates, antibodies and/or anti-body related structures or any combination thereof.
- At least one biomarker, fluorescence marker, dye, spin-label, radioactive marker, metal chelator, antenna chromophore, ligand to a biological receptor, enzyme inhibitor, enzyme substrate, antibody and/or anti-body related structure or any combination thereof is attached to at least some of the functional groups that serves as handles for conjugation.
- the in- vivo use of the nanoparticles of this invention requires them to be formulated according to best practice well known to those skilled in the art.
- Water is a preferred solvent but one or more co-solvents or additives may be added in 0.1-10%) to improve stability in solution.
- Acceptable co solvents would be alcohols like ethanol or glycerol, biocompatible polymers like ethyleneglycol or polyvinyl alcohol, dimethyl sulfoxide, or N-methyl pyrrolidinone. It can also be advantageous to add one or more osmoregulators like mannitol, sorbitol, lactose, glucose or other sugars or sugar alcohols.
- electrolytes may also fulfill the function of a cryoprotectant, enhancing the efficiency of reconstitution after freeze drying. It may also be advantageous to add electrolytes to lower the physiological effects of the injected solution. Preferred electrolytes would be a combination of NaCl, CaCl 2 and MgCl 2 . Regulation of the pH of the injectable solution is preferable and any buffer suitable for injection can be contemplated but preferred is Tris-HCl. Metal ion scavengers can also be contemplated as an additive. Some typical examples would be EDTA
- Example la Production of oleate capped nanoparticles of gadolinium hydroxide.
- Diameter was measured by DLS, volume average 7 nm, Gd 36 % w/w (Method according to A. Barge, G. Cravotto, E. Gianolio and F. Fedeli, Contrast Med. Mol. Imaging 1 : 184-188 (2006)), CI w/w 4.5 % according to Mohr, Water (as volatiles below 200 °C by TGA) 10 % w/w, Ash 44% w/w, Oleate (as determined by HPLC according to Example 8) 40.2 % w/w. TOPO (HPLC) 3 % w/w. Oleyl alcohol ⁇ 0.01% w/w (HPLC).
- Example lc Substituting the 50 mM gadolinium chloride solution for a mixture of 30 mM GdCl 3 and 20 mM TbCl 3 gave analogous nanoparticles with a core of 60% gadolinium hydroxide and 40% terbium hydroxide.
- Example Id Substituting the 50 mM gadolinium chloride solution for a mixture of 30 mM GdCl 3 and 20 mM DyCl 3 gave analogous nanoparticles with a core of 60% gadolinium hydroxide and 40%> dysprosium hydroxide.
- Example lg Preparation of oleate capped nanoparticles in the presence of 1,2- tetradecanediol.
- a 20 ml (0,05M GdCl 3 solution) is heated to 100 °C. During the heating period, 0.1290 g of 1 ,2-Tetradecanediol is added. When the solution reached 100 °C, 177.5 ⁇ oleic acid is added and mixed. In a separate flask, 20 ml of TMAH
- TMAH tetramethylammonium hydroxide
- Example lh Preparation of oleate capped nanoparticles in the presence of oleyl amine.
- a 20 ml (0,05M GdCl 3 solution) is heated to 100 °C. When the solution reached 100 °C, 177.5 ⁇ oleic acid is added and mixed.
- 13.2 ml of TMAH (0.0825 M solution) mixed with 226 ⁇ oleyl amine is heated to 50 °C. After 5 minutes of waiting period, the TMAH solution containing oleyl amine is mixed with the hot GdCl 3 solution containing oleic acid. White precipitate is formed after mixing. Size according to DLS in cyclohexane: 10 nm.
- Example 2a Coating of oleate capped particles with PEG silane.
- Oleate capped particles (250 mg) from example 1 was dissolved in dry THF (tetrahydrofuran) (20 ml). Methoxy(polyethyleneoxy)propyltrimethoxysilane (610 ⁇ , 1.0 mmol, average Mw 550) was added and the reaction mixture was shaken for a few minutes. Then KOt-Bu (120 mg, 1.0 mmol) was added and the mixture was stirred for 48 h at room temperature under N 2 . The resulting mixture was filtered and the filtrate was concentrated at reduced pressure until approximately 2 ml remained. Diethyl ether (20 ml) was added to the concentrated solution whereupon a precipitate formed.
- THF tetrahydrofuran
- Diameter as measured by DLS volume average 8 nm, Gd 20 % w/w.
- Example 2b Coating of oleate capped yttrium hydroxide particles.
- the procedure according to example 2a was carried out on yttrium hydroxide particles prepared according to example If
- Example 3a Hardening of PEG-silane coated particles with
- n-propanol 80% aq. n-PrOH
- DPTS Diethylphosphatoethyl triethoxysilane
- Example 3b Hardening of PEG silane coated particles of Yttrium hydroxide with DPTS.
- DTEP Dimethylphosphatoethyl triethoxysilane
- Bis(triethoxysilyl)methane (306 mg, 0.9 mmol) was added to PEG coated particles (300 mg, example 2a) dissolved in 60 ml aqueous 80%> 1-propanol in a pressure vessel. The reaction mixture was stirred for 48 h at 95 °C and then 24 h at 120 °C. The temperature was lowered to room temperature and the clear solution was filtered (0.2 ⁇ syringe filter). The hardened material is purified using diafiltration as described in Example 6.
- Example 6 Purification by Diafiltration Hardened material (4 ml) from Examples 3-5 was mixed and sonicated for 5 minutes with 41 ml TRIS/HCl buffer (5 mM at pH7,4; 0,2 ⁇ filtered) and subjected to diafiltatration.
- 41 ml TRIS/HCl buffer 5 mM at pH7,4; 0,2 ⁇ filtered
- a 500k NMWC (Nominal Molecular Weight Cut-off) pore size column (GE Healthcare's Midgee ultrafiltration cartridge Model #: UFP-500-C- MM01A) was used and the permeate was collected. About 2 ml retentate was left after the diafiltration process and 43 ml TRIS/HCl buffer was added for another cycle of diafiltration using the same cartridge. The permeate was again collected for this cycle.
- the collected permeates (-86 ml) were subjected to a 10k NMWC pore size diafilter column (GE Healthcare's Midgee ultrafiltration cartridge Model #: UFP- 10-C-MMOl A) to remove the free ions.
- the collected retentate was about 2 ml.
- a ⁇ 7 ml "dead- volume" from the cartridge was washed out with TRIS/HCl buffer, adding up to a total volume of 8-9 ml diafiltered solution.
- the diafilter columns were operated with a typical inlet pressure of 1 bar overpressure.
- the diafiltered sample was later subjected to 0.2 ⁇ syringe filtration before stability or size measurement, to remove unwanted material like dust particles.
- a measured amount of hardened (typically 300 ⁇ ) or diafiltered material (typically 2 ml) is subjected for stability testing at different incubation conditions. Incubation conditions were used: (a) at pH5.8 for Oh; (b) at pH5.8 after lh; (c) at pH5.8 after 24h; (d) at pHl .3 after 24h.
- 300 ⁇ of hardened material or 2 ml of diafiltered material was incubated in a 5 -ml acetate buffer solution (at pH5,8).
- aqueous HC1 (1,0 M) is added to adjust the pH of the buffer. After subjecting the sample to the desired incubation period, the pH of the solutions were adjusted to pH5.8 (if needed) before determining the free gadolinium
- Example 8 Quantitative analysis of Oleate in oleate capped particles from example 1. About 10 mg oleate capped particles were weighed in and dissolved in a mixture of 1.0 ml THF, 1.0 ml formic acid and 1.0 ml water. A 1.0 ml aliquot of this solution was further diluted with 2.0 ml acetonitrile and 1.0 ml water and injected on a HPLC system. (The pump was a Varian 9010 and the detector an Alltech ELSD 2000 with the temperature set to 50 °C and the gas flow set to 1.5 1/min. The column was YMC Hydrosphere 150 x 4.6 mm.
- the mobile phase consisted of 90 % acetonitrile and 10 % Water containing 1 % formic acid. Since this type of detector only can be considered to be linear within a short range, two standards of oleic acid were prepared with a concentration close (one slightly higher and one slightly lower) to the expected concentration of oleic acid in the sample. Three injection of were made for each of the standards and the sample and the areas under the peaks were integrated. The concentration in the sample solution was determined through linear interpolation. The percentage of oleic acid in the particles was calculated from the amount of particles dissolved and the dilution of the sample.
- Example 9 Pharmacological formulation of nanoparticles according to example 6.
- a solution from the diafiltration process in example 6 was analyzed for gadolinium and the volume was reduced by spin filtration on a lk cut-off filter so the
- Example 10 Aminopropylation of Gd(OH)3 particles.
- Aminopropyltrimethoxysilane (0.14 ⁇ ,, 0.76 ⁇ ) was added to 2 ml solution of hardened particles (example 4). The solution was shaken at 95 °C for 16 h. Tris/HCl buffer (0.5 ml, pH 7.4) was added to the solution, which was then concentrated in a stream of nitrogen until 1 ml remained. The particles were purified on a Sephadex G- 25 short column (PD-10, GE) eluting with H 2 0. In total, 3 ml of an aqueous particle solution was collected.
- PD-10, GE Sephadex G- 25 short column
- Zinc powder (20 mg) was added to N,N-didansylcystine (2 mg) dissolved in 0.5% trifluoracetic acid in acetonitrile (1 ml). The reaction mixture was shaken at room temperature for 1 h and then filtered. The yellow filtrate was used without any further purification.
- 6-Maleimidohexanoic acid N-hydroxysuccinimide ester (10 ⁇ , 3 ⁇ / ⁇ in DMF) was added to gel- filtrated (H 2 0, GE, PD-10) aminopropylated particles (1 ml) and then shaken at room temperature for 18 h.
- the mixture was gel- filtrated (GE, PD-10, H 2 0) and the Gd-positive fractions (2 and 3) were combined.
- the pH of the combined fractions was corrected with PBS buffer (0.5 ml, pH 7.4) and N- dansylcysteine solution (40 ⁇ ) was added.
- the mixture was shaken at room temperature for 18 h and then gel- filtrated (H 2 0, GE, PD-10).
- E xam ple 12 Synth e sis o f ( l-trimethoxysilyl)propyl-3-Tri-m-PEG 4 (3,3- dimethoxy-9,9-di-2,5,8,ll,14-pentaoxapentadecyl-2,7,ll,14,17,20,23-heptaoxa-3- silatetracosane)
- Example 12a 3-(3-bromo-2,2-bis(bromomethyl)propoxy)prop-l-ene.
- Example 12b 16-(allyloxymethyl)-16-2,5,8,ll,14-pentaoxapentadecyl- 2,5,8,11, 14,18,21,24,27,30-decaoxahentriacontane.
- Tetraethyleneglycol monomethyl ether (1.91 ml, 9 mmol) dissolved in dry and degassed DMF (3.5 ml, dried 24h, 4A MS) was added carefully to sodium hydride (365 mg, 9 mmol) in dry and degassed DMF (15 ml, dried 24h, 4A MS) under nitrogen at 0 °C using a syringe. The temperature was then raised to room temperature and the reaction mixture was stirred for another 30 min. 3-(3-bromo-2,2- bis(bromomethyl)propoxy)prop-l-ene (730 mg, 2.0 mmol) was then added and the temperature was raised to 100 °C.
- Example 12c 3,3-dimethoxy-9,9-di-2,5,8,ll,14-pentaoxapentadecyl-
- Example 13 TriPEG coated nanoparticles. Oleate capped particles (175 mg) from example la was dissolved in dry THF (15 ml). The material from example 12c; 3,3- dimethoxy-9,9-di-2,5,8, 11 , 14-pentaoxapentadecyl-2,7, 11,14,17,20,23-heptaoxa-3- silatetracosane (830mg, 0.7 mmol) was added and the reaction mixture was shaken for a few minutes. Potassium tert-butoxide (84 mg, 0.7 mmol) was added and the mixture was stirred for 48 h at room temperature under nitrogen.
- Example 15a Allyl-3-(2,5,8,ll,14,17,20,23-octaoxapentacosan-25-yl)urea.
- Allyl isocyanate 400 ⁇ , 4.6 mmol
- 2,5,8,11,14, 17,20,23-octaoxapentacosan- 25-amine 550 mg, 1.4 mmol
- the reaction mixture was shaken at 50 °C for 18h.
- the volatile materials were removed at reduced pressure to give a dark yellow oil (670 mg, >95% yield), which was used without any further purifications.
- Example 15c l-(2,5,8,ll,14,17,20,23-octaoxapentacosan-25-yl)-3-(3-(trimethoxy- silyl)propyl)urea.
- K ar s t e dt ' s c at a l y s t ( P l at i num ( 0 )-l,3-divinyl-l, 1,3,3- tetramethylsiloxane ) ( 2 0 ⁇ 1 , 2 % i n xylene) was added to Allyl-3- (2,5,8,1 l,14,17,20,23-octaoxapentacosan-25-yl)urea (117 mg, 0.25 mmol, example 15b) and trimethoxysilane (192 ⁇ , 1.5 mmol) in dry toluene (1 ml) under nitrogen at room temperature.
- the reaction mixture was shake
- Bis(triethoxysilyl)methane ( 7.7 mg, 0.0225 mmol) was added to PEG coated particles (30 mg) dissolved in 6 ml aqueous 80% 1-Propanol in a pressure vessel. The reaction mixture was stirred for 46h at 95°C and then 24h at 120°C. The temperature was lowered to room temperature and the clear solution was filtered (0.2 ⁇ syringe filter). A fraction of the filtrate (5 ml) was diluted with TRIS/HCl buffer (95 ml, 5 mM pH7.4) and then filtered using 500k NMWC pore-size column (GE Heathcare's Midgee ultrafiltration cartridge Model: UFP-500-C-MM01A).
- Bis(triethoxysilyl)methane ( 15.3 mg, 0.045 mmol) was added to PEG coated particles (30 mg) dissolved in 6 ml aqueous 80%> 1-Propanol in a pressure vessel. The reaction mixture was stirred for 46h at 95°C and then 24h at 120°C. The temperature was lowered to room temperature and the clear solution was filtered (0.2 ⁇ syringe filter). A fraction of the filtrate (5 ml) was diluted with TRIS/HCl buffer (95 ml, 5 mM pH7.4) and then filtered using 500k NMWC pore-size column (GE Heathcare's Midgee ultrafiltration cartridge Model: UFP-500-C-MM01A).
- the collected permeates ( ⁇ 96 ml) were then filtered using a 300k NMWC pore size diafilter column (GE Heathcare's Midgee ultrafiltration cartridge Model: UFP-300-C-MM01A) to remove the free ions and concentrate the particles.
- the retentate was collected and then filtered using a syringe filter (0.2 ⁇ ).
- Bis(triethoxysilyl)methane (23 mg, 0.0675 mmol) was added to PEG coated particles (30 mg) dissolved in 6 ml aqueous 80% 1-Propanol in a pressure vessel. The reaction mixture was stirred for 46h at 95°C and then 24h at 120°C. The temperature was lowered to room temperature and the clear solution was filtered (0.2 ⁇ syringe filter). A fraction of the filtrate (5 ml) was diluted with TRIS/HCl buffer (95 ml, 5 mM pH7.4) and then filtered using 500k NMWC pore-size column (GE Heathcare's Midgee ultrafiltration cartridge Model: UFP-500-C-MM01A).
- Bis(triethoxysilyl)methane ( 27.6 mg, 0.081 mmol) was added to PEG coated particles (30 mg) dissolved in 6 ml aqueous 80%> 1-Propanol in a pressure vessel. The reaction mixture was stirred for 46h at 95°C and then 24h at 120°C. The temperature was lowered to room temperature and the clear solution was filtered (0.2 ⁇ syringe filter). A fraction of the filtrate (5 ml) was diluted with TRIS/HCl buffer (95 ml, 5 mM pH7.4) and then filtered using 500k NMWC pore-size column (GE Heathcare's Midgee ultrafiltration cartridge Model: UFP-500-C-MM01A).
- the collected permeates ( ⁇ 96 ml) were then filtered using a 300k NMWC pore size diafilter column (GE Heathcare's Midgee ultrafiltration cartridge Model: UFP-300-C-MM01A) to remove the free ions and concentrate the particles.
- the retentate was collected and then filtered using a syringe filter (0.2 ⁇ ).
Abstract
La présente invention concerne des nanoparticules paramagnétiques qui peuvent être utilisées comme agents de contraste pour visualiser ou réaliser l'imagerie d'un matériel biologique. Lesdites nanoparticules comprennent un cœur d'hydroxyde d'élément terre rare amorphe et une écorce organique comprenant des atomes de silicium et des atomes de phosphore. De préférence, l'écorce comprend une monocouche orientée d'un ou plusieurs résidus organo-oxysilanes. Un second silane, se liant entre les organo-oxysilanes plus grands, peut être ajouté afin de stabiliser l'écorce. L'invention concerne des procédés de préparation desdites nanoparticules.
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