Luminescent particles based on rare earth elements and use thereof as a diagnostic agent

Patent metadata

Field	Value
Publication number	US-11401463-B2
Application number	US-201816614055-A
Country	US
Kind code	B2
Filing date	May 18, 2018
Priority date	May 18, 2017
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

The present invention concerns a luminescent particle comprising a nanoparticle of formulaA1-xLnxVO4(1-y)(PO4)y  (I)in which A is selected from yttrium (Y), gadolinium (Gd), lanthanum (La), and mixtures thereof; Ln is selected from europium (Eu), dysprosium (Dy), samarium (Sm), neodymium (Nd), erbium (Er), ytterbium (Yb), and mixtures thereof; 0<x<1; and 0≤y<1; characterized in that the nanoparticle on its surface has tetraalkylammonium cations in an amount such that said nanoparticle has a zeta potential, ζ, of less than or equal to −28 mV in an aqueous medium with a pH≥5, more particularly with a pH≥5.5, and with an ionic conductivity >100 μS·cm−1.It also concerns a method for preparing such luminescent particles, a colloidal suspension of these particles, and the use thereof as a diagnostic agent, and also a diagnostic kit comprising such luminescent particles.

First claim

The invention claimed is:

1. A luminescent particle comprising a nanoparticle of formula:
A 1-x Ln x VO 4(1-y) (PO 4 ) y   (I)

in which:
A is selected from yttrium (Y), gadolinium (Gd), lanthanum (La), and mixtures thereof;
Ln is selected from europium (Eu), dysprosium (Dy), samarium (Sm), neodymium (Nd), erbium (Er), ytterbium (Yb), and mixtures thereof;
0<x<1; and
0≤y<1;

wherein the nanoparticle has, at the surface, tetraalkylammonium cations in an amount such that said nanoparticle has a zeta potential, ζ, of less than or equal to −28 mV in an aqueous medium with a pH≥5, and with an ionic conductivity of strictly less than 100 μS·cm −1 .

2. The particle as claimed in claim 1 , wherein said tetraalkylammonium cations are associated with the nanoparticle via electrostatic interactions with the negatively charged O 2− surface ions of the nanoparticle.

3. The particle as claimed in claim 1 , wherein said tetraalkylammonium cations are cations of formula NR 4 + where R, which are identical or different, represent a C 1 -C 6 -alkyl.

4. The particle as claimed in claim 1 , wherein said tetraalkylammonium cations are selected from tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, and mixtures thereof.

5. The particle as claimed in claim 1 , wherein said nanoparticle has a zeta potential ζ of less than or equal to −30 mV in an aqueous medium with a pH≥6.5, and with an ionic conductivity of strictly less than 100 μS·cm −1 .

6. The particle as claimed in claim 1 , said nanoparticle being of formula (I′)
A 1-x Ln x VO 4(1-y) (PO 4 ) y ·(NR 4 + ) z   (I′)

in which:
A is selected from Y, Gd, La, and mixtures thereof;
Ln is selected from Eu, Dy, Sm, Nd, Er, Yb, and mixtures thereof;
0<x<1;
0≤y<1;
R, which are identical or different, represent a C 1 -C 6 -alkyl; and
z represents the number of tetraalkylammonium cations NR 4 + located on the surface of said nanoparticle.

7. The particle as claimed in claim 1 , wherein y is 0.

8. The particle as claimed in claim 1 , wherein A represents Y.

9. The particle as claimed in claim 1 , wherein Ln represents Eu.

10. The particle as claimed in claim 1 , wherein said nanoparticle is of formula Y 1-x Eu x VO 4 ·(NR 4 + ) z (III′), in which:
0<x<1;
R, which are identical or different, represent a C 1 -C 6 -alkyl
z represents the number of tetraalkylammonium cations NR 4 + located on the surface of said nanoparticle.

11. The particle as claimed in claim 1 , wherein the nanoparticle of formula (I) has an elongated ellipsoidal shape.

12. The particle as claimed in claim 1 , wherein the product of the degree of doping, x, with Ln ions, and the quantum yield of the emission by the nanoparticle is maximized.

13. The particle as claimed in claim 1 , wherein said nanoparticle is coupled to at least one targeting agent.

14. A method for preparing luminescent particles comprising a nanoparticle of formula:
A 1-x Ln x VO 4(1-y) (PO 4 ) y   (I)

in which:
A is selected from yttrium (Y), gadolinium (Gd), lanthanum (La), and mixtures thereof;
Ln is selected from europium (Eu), dysprosium (Dy), samarium (Sm), neodymium (Nd), erbium (Er), ytterbium (Yb), and mixtures thereof;
0<x<1; and
0≤y<1;
by coprecipitation reaction, in aqueous medium, from precursors of said elements A and Ln, and in the presence of orthovanadate (VO 4 3− ) and optionally phosphate (PO 4 3− ) ions;
said reaction being performed in the presence of an effective amount of tetraalkylammonium cations such that said nanoparticle has a zeta potential, ζ, of less than or equal to −28 mV in an aqueous medium with a pH≥5, and with an ionic conductivity of strictly less than 100 μS·cm −1 .

15. The method as claimed in claim 14 , said method comprising at least the steps of:
(i) providing an aqueous solution, called solution (1), comprising orthovanadate ions (VO 4 3− ), and optionally phosphate ions (PO 4 3− ), and tetraalkylammonium cations;
(ii) admixing the aqueous solution (1) with an aqueous solution, called solution (2), comprising said precursors of the elements A and Ln, under conditions conducive to the formation by coprecipitation of the nanoparticles of formula (I); and
(iii) recovering the nanoparticles of formula (I) with tetraalkylammonium cations located on their surface that are formed at the end of step (ii).

16. The method as claimed in claim 14 , wherein the tetraalkylammonium cations are selected from tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, and mixtures thereof.

17. The method as claimed in claim 14 for preparing particles of formula (I′)
A 1-x Ln x VO 4(1-y) (PO 4 ) y ·(NR 4 + ) z   (I′)

in which:
A is selected from Y, Gd, La, and mixtures thereof;
Ln is selected from Eu, Dy, Sm, Nd, Er, Yb, and mixtures thereof;
0<x<1;
0≤y<1;
R, which are identical or different, represent a C 1 -C 6 -alkyl; and
z represents the number of tetraalkylammonium cations NR 4 + located on the surface of said nanoparticle.

18. The method as claimed in claim 14 , wherein the orthovanadate ions (VO 4 3− ) are generated in situ by reacting a metavanadate salt, with a base.

19. The method as claimed in claim 14 , said method further comprising one or more steps of coupling the particles with one or more targeting agents.

20. A colloidal aqueous suspension comprising particles as defined in claim 1 .

21. A method of diagnostics, comprising:
coupling the luminescent particles as defined in claim 1 to one or more targeting agents of a substance of biological or chemical interest to obtain a diagnostic probe;
implementing said diagnostic probe in an in vitro, ex vivo, or in vivo diagnostic technique; and
detecting and/or quantifying said substance of biological or chemical interest.

22. A diagnostic kit comprising at least particles as defined in claim 1 , or a colloidal aqueous suspension of these particles.

23. The particle as claimed in claim 6 , wherein z is between 100 and 10,000.

24. A colloidal aqueous suspension comprising particles obtained by the method defined in claim 14 .

25. A method of diagnostics, comprising:
coupling the luminescent particles obtained by the method of claim 14 to one or more targeting agents of a substance of biological or chemical interest to obtain a diagnostic probe;
implementing said diagnostic probe in an in vitro, ex vivo, or in vivo diagnostic technique; and
detecting and/or quantifying said substance of biological or chemical interest.

26. A diagnostic kit comprising at least particles obtained by the method defined in claim 14 , or a colloidal aqueous suspension of these particles.

Assignees

• Ecole Polytech
• Centre Nat Rech Scient

Inventors

• Gacoin Thierry
• Richly Maximilian
• Preira Pascal
• Alexandrou Antigoni
• Bouzigues Cédric
• Mohammedi Rabei

Classifications

• A61K49/101

  the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals · CPC title

• G01N2458/40

  Rare earth chelates · CPC title

• C09K11/025 Primary

  non-luminescent particle coatings or suspension media · CPC title

• C01P2006/40

  Electric properties · CPC title

• C01F1/00

  Methods of preparing compounds of the metals beryllium, magnesium, aluminium, calcium, strontium, barium, radium, thorium, or the rare earths, in general · CPC title