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WO2018171882A1 - Magnetofluorescent nanoparticles - Google Patents

Magnetofluorescent nanoparticles Download PDF

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Publication number
WO2018171882A1
WO2018171882A1 PCT/EP2017/056893 EP2017056893W WO2018171882A1 WO 2018171882 A1 WO2018171882 A1 WO 2018171882A1 EP 2017056893 W EP2017056893 W EP 2017056893W WO 2018171882 A1 WO2018171882 A1 WO 2018171882A1
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Prior art keywords
nanoparticles
gdaxb
blu
core
doped
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PCT/EP2017/056893
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French (fr)
Inventor
Thomas JÜSTEL
Sara ESPINOZA VILLALBA
Matthias Müller
R. Rox Anderson
Martin Purschke
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Fachhochschule Muenster
General Hospital Corp
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Fachhochschule Muenster
General Hospital Corp
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Priority to PCT/EP2017/056893 priority Critical patent/WO2018171882A1/en
Publication of WO2018171882A1 publication Critical patent/WO2018171882A1/en
Anticipated expiration legal-status Critical
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/0002General or multifunctional contrast agents, e.g. chelated agents
    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09KMATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • C09K11/77Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals
    • C09K11/7766Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals containing two or more rare earth metals
    • C09K11/77742Silicates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/001Preparation for luminescence or biological staining
    • A61K49/0063Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0065Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/06Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818Nuclear 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
    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09KMATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • C09K11/77Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals
    • C09K11/7766Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals containing two or more rare earth metals
    • C09K11/7777Phosphates
    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09KMATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • C09K11/77Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals
    • C09K11/7766Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals containing two or more rare earth metals
    • C09K11/778Borates

Definitions

  • Example III refers to (Luo.98Pro.oiGdo.oi) 2 Si05 which was made the following way:

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nanotechnology (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Luminescent Compositions (AREA)

Abstract

The present invention relates to nanoparticles which are doped with Gd 3+ so they are capable of emitting UV-radiation but also paramagnetic and detectably by MR techniques.

Description

Magnetofluorescent Nanoparticles
D e s c r i p t i o n The present invention relates to the field of nanoparticles, especially nanoparticles which are capable of emitting UV radiation
These materials are interesting especially for medical applications due to their possible use in radiation therapy. However, the localization of these particles inside tissue and/or the human body is not always easily possible.
Therefore it is an object to provide improved nanoparticles which also allow improved localization and/or direction. This object is solved by claim 1 of the present invention.
Accordingly nanoparticles are provided, which comprise a host material with an optical band gap of > 5.0 eV doped with Gd3+. The term„nanoparticles" in the context of the present invention especially means and/or includes particles with a mean diameter from > 10 and < 2000 nm, preferred > 50 and < 1000 nm, more preferably from >100 and < 500 nm. Surprisingly it has been found that with these nanoparticles it is possible for many
applications to provide particles which are capable of emitting UV radiation, but in the same course, especially due to the dotation with Gd3+ are paramagnetic and also suspectible to magneto resonance (MR) imaging techniques. Furthermore for many applications within the present invention, one or more of the following advantages can be observed
Higher contrast of MR images
Faster detection of tissue to be cured
Faster imaging process in general, which reduces stress to the patient
- Higher resolution of MR images
According to a preferred embodiment of the present intention, the host material is selected from aluminates, borated, fluorides, phosphates, sulfates or mixtures thereof. According to a preferred embodiment of the present invention, the host material is co-doped with Pr3+, Nd3+, Bi3+ or a mixture thereof. This has been shown to be advantageous for many applications within the present invention.
According to a preferred embodiment of the present invention, the nanoparticles comprise one or more of the following materials: (Yi-y-z-a-bLuyLazGdaXb)P04, (Yi-y-z-a-bLuyLazGdaXb)B03,
(Yl_y_z_a-bLUyLatGdaXb)MgB5Ol0, (Yl-y-t-a-bLUyLazGdaXb)3Al50l2, (Yl-x-y-a- bLuxLayGdaXb)2Si05,
Figure imgf000004_0001
(Mi-yYy/2Ay/2)Li2Si04, A(Yi_y_
LuyLazGdaXb)F4, A(Yi-y-zLuyLazGdaXb)3Fio, or Ba(Yi-y-zLuyLazGdaXb)2Fio, with - for each structure independently from each other - y, z > 0 and < 1, a > 0 and < 1, preferably > 0.1 and < 0.5, b > 0 and < 1, so that y + z + a + b < 1, M = Ca, Sr, A = Li, Na, K, Rb, Cs, X = Pr, Nd, Bi. According to a preferred embodiment the nanoparticles comprise a core- shell structure with a core and at least one shell, whereby the core comprises, preferably consists essentially of a magnetic material and at least one shell comprises, preferably consists essentially of the host material with an optical band gap of > 5.0 eV doped with Gd3+. This has been found to be advantageous for many applications within the present invention.
The term "consisting essentially of in the context of the present invention especially means and/or includes > 95 wt-%, more preferred > 98 wt-% and most preferred > 99 wt-%. The magnetic material of the core preferably comprises, more preferably consists essentially of a material selected from the group comprising Fe304, Y-Fe203 (maghemite), Nd2Fei4B, SmCo5, Sm2Coi7, Cr02 or mixtures thereof.
According to a preferred embodiment of the present invention, the nanoparticles comprise at least two shells, whereby the outer shell comprises, preferably consists essentially of a UV- transparent and water insoluble material, preferably a material selected out of the group comprising MgAl204, A1203, Zr02, Si02, or mixtures thereof.
The term "UV transparent" in the context of the present invention especially means and/or includes materials that absorb UV radiation in the range between 200 and 400 nm to less than 20 %, more preferably less than 5%.
The term "water insoluble" in the context of the present invention especially means and/or includes that the PKL value of the solubility product of the material in water is larger than 10. According to a preferred embodiment of the present invention the core of the nanoparticles has a mean diameter of > 1 and < 100 nm. This has been shown to be advantageous for many applications within the present invention.
According to a preferred embodiment of the present invention, the mean diameter of the nanoparticles is > 10 and < 500 nm.
The present invention furthermore relates to the use of the inventive nanoparticles for medical imaging, medical treatment and/or simultaneous medical and imaging.
The present invention furthermore relates to a method of medical imaging, involving methods relying on magnetic resonance (MR) techniques. To this end, the a suspension of the particles is injected into the patient, which leads to an enhanced contrast in those areas, where the particles are agglomerated.
The aforementioned components, as well as the claimed components and the components to be used in accordance with the invention in the described embodiments, are not subject to any special exceptions with respect to their size, shape, material selection and technical concept such that the selection criteria known in the pertinent field can be applied without limitations.
Additional details, characteristics and advantages of the object of the invention are disclosed in the subclaims and the following description of the respective figures—which in an exemplary fashion— show preferred embodiments according to the invention. Such
embodiment does not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the present invention as claimed. In the Figures
Fig 1 shows the excitation and emission spectrum of a nanoparticle material according to a first embodiment of the present invention;
Fig 2 shows the excitation and emission spectrum of a nanoparticle material according to a second embodiment of the present invention; and Fig 3 shows the excitation and emission spectrum of a nanoparticle material according to a third embodiment of the present invention.
The invention is in the following described by the Examples I to III which are purely illustrative and non-limiting:
Example I:
Example I relates to Luo.98Pro.oiGdo.oiB03 which was made as follows: The starting materials 11.6992 g (29.4 mmol) Lu203, 0.1087 g (0.3 mmol) Gd203, 0.2610 g (0.6 mmol) Pr(N03)3-6H20, and 4.4520 (72 mmol) H3B03 are blended in acetone using an agate mortar until the acetone is completely evaporated. To compensate the loss of Boron due to the formation of HB02 during the calcination, a B-excess of 20% is used. The obtained powder blend is filled into a corundum crucible and is calcined at 800 °C for 1 h in air. During the calcination the crucible is sealed with a lid. Afterwards the pre-calcined powder is ground and subsequently annealed at 1200 °C for 12 h in a CO atmosphere. Therefore, the powder is filled into a corundum crucible which is imbedded in a larger corundum crucible filled with active carbon. During calcination the larger crucible is sealed with a lid. Phase purity of the obtained product is investigated using x-ray powder diffraction. The average particle size is in the range of 100 - 2000 nm.
Fig. 1 shows the excitation and emission spectrum of this material.
Example II
Example II relates to Luo.98Pro.oiGdo.oiP04 which was made as follows: The starting materials 9.7493 g (24.5 mmol) Lu203, 0.0906 g (0.25 mmol) Gd203, 0.2175 g (0.5 mmol) Pr(N03)3-6H20, and 6.6028 (50 mmol) (NH4)2HP0 are blended in acetone using an agate mortar until the acetone is completely evaporated. 0.2694 g (10.3865 mmol, 2 mass- %) LiF is used a flux. The obtained powder blend is filled into a corundum crucible and is calcined at 1200 °C for 8 h in a CO atmosphere. Therefore, the powder is filled into a corundum crucible which is imbedded in a larger corundum crucible filled with active carbon. During calcination the larger crucible is sealed with a lid. Phase purity of the obtained product is investigated using x-ray powder diffraction. The average particle size is in the range of 100 - 2000 nm. Fig. 2 shows the excitation and emission spectrum of this material. Example III
Example III refers to (Luo.98Pro.oiGdo.oi)2Si05 which was made the following way:
The starting materials 11.6992 g (29.4 mmol) Lu203, 0.1087 g (0.3 mmol) Gd203, and 0.2610 g (0.6 mmol) Pr(N03)3-6H20 are solved in hot, diluted HN03 (solution 1). Simultaneously, 15.13 g (30 mmol) C2H204-2H20 is solved in water (solution 2). After solution 1 is cooled to room temperature, solution 2 is added dropwise to solution 1 to precipitate the solved starting materials as oxalates. Following this, 1.8025 (30 mmol) S1O2 and 0.2742 g (7.4 mmol, 2 mass-%) NH4F are added to the obtained suspension. NH4F is used as a flux. The suspension is transferred into a crystallizing dish and dried at 150 °C in a compartment drier. The obtained powder is filled into a corundum boat and calcined at 1000 °C for 3 h in air. The pre- calcined powder is ground and finally calcined at 1600 °C for 6 h in a reductive forming gas flow (5% H2/95% N2). Phase purity of the obtained product is investigated using x-ray powder diffraction. The average particle size is in the range of 100 - 2000 nm.
Fig. 3 shows the excitation and emission spectrum of this material.
The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the foregoing description is by way of example only and is not intended as limiting. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. The invention's scope is defined in the following claims and the equivalents thereto. Furthermore, reference signs used in the description and claims do not limit the scope of the invention as claimed.

Claims

C l a i m s
Nanoparticles which comprise a host material with an optical band gap of > 5.0 eV doped with Gd3+
The nanoparticles of Claim 1, whereby the host material is selected from aluminates, borated, fluorides, phosphates, sulfates or mixtures thereof.
The nanoparticles of Claim 1 or 2, whereby the host material is co-doped with Pr3+, Nd3+, Bi3+, or a mixture thereof
The nanoparticles of any of the claims 1 to 3, whereby the the nanoparticles comprise one or more of the following materials: Yi-y-z-a-bLuyLazGdaXb)P04, (Yi-y-z-a- bLuyLazGdaXb)B03, (Yi-y-z-a-bLuyLatGdaXb)MgB5Oio, (Yi-y-t-a-bLuyLazGdaXb)3Al50i2, (Yi_x_y_a-bLuxLayGdaXb)2Si05, (Yi-x-y-a-bLuxLayGdaXb)2Si207, (Mi-yYy/2Ay/2)Li2Si04, A(Yi-y-LuyLazGdaXb)F4, A(Yi-y-zLuyLazGdaXb)3Fio, or Ba(Yi-y-zLuyLazGdaXb)2Fio, with - for each structure independently from each other - y, z > 0 and < 1, a > 0 and < 1, preferably > 0.1 and < 0.5, b > 0 and < 1, so that y + z + a + b < 1, M = Ca, Sr, A = Li, Na, K, Rb, Cs, X = Pr, Nd, Bi.
The nanoparticles of any of the claims 1 to 4, whereby the nanoparticles comprise a core- shell structure with a core and at least one shell, whereby the core comprises, a magnetic material and at least one shell comprises the host material with an optical band gap of > 5.0 eV doped with Gd3+
The nanoparticles of any of the claims 1 to 5, whereby the magnetic material of the core comprises a material selected from the group comprising Fe304, y-Fe203 (maghemite), Nd2Fei4B, SmCos, Sm2Coi7, CrC or mixtures thereof The nanoparticles of any of the claims 1 to 6, whereby the nanoparticles comprise at least two shells, whereby the outer shell comprises a UV-transparent and water insoluble material.
Use of nanoparticles according to any of the claims 1 to 7 for medical imaging, medical treatment and/or simultaneous medical treatment and imaging.
Use of a isotonic suspension of the nanoparticles according to any of the claims 1 to 7 for injection into a patient prior to a medical diagnostic process, e.g. for contrast enhancement in MR imaging
PCT/EP2017/056893 2017-03-22 2017-03-22 Magnetofluorescent nanoparticles Ceased WO2018171882A1 (en)

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WO2013001444A1 (en) * 2011-06-29 2013-01-03 Koninklijke Philips Electronics N.V. Luminescent material particles comprising a coating and lighting unit comprising such luminescent material
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US8636921B1 (en) * 2012-10-23 2014-01-28 Industrial Technology Research Institute Phosphate phosphor and UV light-emitting device utilizing the same
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US20090226724A1 (en) * 2005-11-28 2009-09-10 National Research Council Of Canada Multifunctional nanostructure and method
US20090014685A1 (en) * 2006-03-06 2009-01-15 Koninklijke Philips Electronics N.V. Luminescent material using (y, gd)-containing nanoparticle and surface bound organtic ligands
WO2013001444A1 (en) * 2011-06-29 2013-01-03 Koninklijke Philips Electronics N.V. Luminescent material particles comprising a coating and lighting unit comprising such luminescent material
US20130115172A1 (en) * 2011-11-08 2013-05-09 Korea Institute Of Science And Technology Magnetic nanophosphor having core/shell structure and the synthetic method thereof
US8636921B1 (en) * 2012-10-23 2014-01-28 Industrial Technology Research Institute Phosphate phosphor and UV light-emitting device utilizing the same
CN103623437B (en) * 2013-12-01 2015-08-19 中国科学院上海硅酸盐研究所 A kind of imaging nano-probe material and its preparation method and application

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Title
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SHAN LU ET AL: "Multifunctional Nano-Bioprobes Based on Rattle-Structured Upconverting Luminescent Nanoparticles", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 54, no. 27, 26 May 2015 (2015-05-26), pages 7915 - 7919, XP055430878, ISSN: 1433-7851, DOI: 10.1002/anie.201501468 *

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