Novel compositions magnetic particles covered with gem-bisphosphonate derivatives

• US 20040253181A1
• Filed: 12/19/2003
• Published: 12/16/2004
• Est. Priority Date: 12/20/2002
• Status: Active Grant

• Current Assignee: Guerbet
• Original Assignee: Guerbet
• Inventors: Raynal, Isabelle, Rousseaux, Olivier, Port, Marc, Corot, Claire
• Granted Patent: US 7,780,953 B2
• Time in Patent Office: Days
• US Class Current: 424/9.3
• CPC Class Codes: A61K 49/1842 the small organic molecule being a phosphate or a phosphonate, not being a phospholipid
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The invention relates to a composition comprising acid magnetic particles (p) based on an iron compound, the acid magnetic particles (p) being complexed by one or more gem-bisphosphonate compounds, of formula I

X-L-CH(PO₃H₂)₂  (I)

in which

L represents an organic group connecting the X group to the gem-bisphosphonate group —CH(PO₃H₂)₂;

X represents a chemical group capable of reacting with a biovector; all or some of the X groups of the particles optionally being coupled to a biovector.

The invention relates also to a process for the preparation of the compositions and their use, in particular as contrast products for Magnetic Resonance Imaging (MRI).

Claims

1. A composition comprising acid magnetic particles (p) based on an iron compound, said acid magnetic particles (p) being complexed by one or more gem-bisphosphonate compounds, of formula I:

X-L-CH(PO₃H₂)₂ 

 

(I)

in which;

L represents an organic group connecting the x group to the gem-bisphosphonate group —

CH(PO₃H₂)₂;

X represents a chemical group capable of reacting with a biovector;

all or some of said X groups of said particles optionally being coupled to a biovector.

2. The composition as claimed in claim 1, in which all or some of the X groups are coupled to a biovector.

3. The composition as claimed in claim 1, in which L is selected from an aliphatic;

alicyclic;

aromatic;

alicyclic-aliphatic;

aromatic-aliphatic group, it being optionally possible for said groups to be substituted by a methyl, hydroxy, methoxy, acetoxy, amido group or a chlorine, iodine or bromine atom;

or else a group -L₁-NHCO-L₂ where L₁ and L₂ are either identical or different and represent an aliphatic;

alicyclic;

aromatic;

alicyclic-aliphatic or aromatic-aliphatic group, it being optionally possible for said groups to be substituted by methyl, hydroxyl, methoxy, acetoxy, amido group or a chlorine, iodine or bromine atom.

4. The composition as claimed in claim 1, in which L represents an optionally substituted phenylene group, it being possible for the X and gem-bisphosphonate groups to be in the ortho, meta or para position.

5. The composition as claimed in claim 1, in which the group L represents an aliphatic group.

6. The composition as claimed in claim 1, in which the group L represents a group —

(CH₂)_p, where p is an integer from 1 to 5.

7. The composition as claimed in claim 1 in which the group L represents L₁-CONH-L₂, L₁ and L₂ being as defined in claim 3.

8. The composition as claimed in claim 1, in which L represents a group —

(CH₂)_m—

CONH—

(CH₂)_n where m and n represent an integer from 0 to 5.

9. The composition as claimed in claim 1, in which X is selected from —

COOH, —

NH₂, —

NCS, —

NH—

NH₂, —

CHO, maleimidyl, alkylpyrocarbonyl, acylazidyl, iminocarbonate, vinylsulfuryl, pyridyldisulfuryl, haloacetyl, dichlorotriazinyl and halogen.

10. The composition as claimed in claim 1, in which X represents —

COOH or —

NH₂.

11. The composition as claimed in claim 1, in which all or some of the compounds of formula (I) have the formula (Ia) below:

HOOC—

(CH₂)₂—

CH(PO₃H₂)₂ 

 

(Ia)

12. The composition as claimed in claim 1, in which the particles (p) are, on average, complexed on at least 90% of their protonated sites by compounds of formula (I).

13. The composition as claimed in claim 1, in which the protonated sites are complexed by at least two gem-bisphosphonate compounds of formula (I) having a different structure.

14. The composition as claimed in claim 1, in which the protonated sites are complexed by at least two compounds of formula (I) having an identical structure.

15. The composition as claimed in claim 1 in which all or some of the magnetic particles (p) are composed of iron hydroxide, of iron hydroxide hydrate, of ferrite, of mixed iron oxides or of a mixture thereof.

16. The composition as claimed in claim 1, in which all or some of the magnetic particles (p) are composed of a ferrite.

17. The composition as claimed in claim 1, in which the ferrite is maghemite or magnetite or a mixture thereof.

18. The composition as claimed in claim 1, in which the particles (p) are superparamagnetic.

19. The composition as claimed in claim 1, in which between 1 and 70% of the X groups of compounds of formula (I) are coupled to a biovector.

20. The composition as claimed in claim 1, in which the X groups of compounds of formula (I) are coupled to at least two different biovectors.

21. The composition as claimed in claim 1, in which the biovector is selected from proteins, optionally recombinant or mutated, glycoproteins, lectins, biotin, vitamins, phospholipids, folic acid derivatives, antibodies or antibody fragments, peptides and derivatives thereof, monosaccharides or polysaccharides, avidin, streptavidin, receptor substrates or inhibitors, steroids and analogs thereof, oligonucleotides, ribonucleic acid sequences, deoxyribonucleic acid sequences, hormones or hormone-like substances, amino acids and derivatives, organic molecules with pharmacological activity, amino alcohols, integrin-targeting agents and MMP-targeting agents.

22. The composition as claimed in claim 1, in which the biovector represents a peptide derivative.

23. The composition as claimed in claim 1 in which the biovector represents an antifolic or folic acid derivative.

24. The composition as claimed in claim 1, in which the biovector represents a phospholipid derivative, in particular a derivative of phosphatidylserine, of phosphatidylethanolamine, of phosphatidylcholine, of phosphatidylinositol or of sphingomyelin or ceramide derivatives.

25. The composition as claimed in claim 1, in which the biovector represents a protein, optionally recombinant or mutated.

26. The composition as claimed in claim 1, in which the biovector represents an antibody or an antibody fragment which is optionally functionalized.

27. The composition as claimed in claim 1, in which the biovector represents an optionally functionalized pharmacophore.

28. The composition as claimed in claim 1, in which the biovector is selected from the amino alcohols of formula (II)

29. The composition as claimed in claim 1, in which the biovector is selected from aminopolyethylene glycols.

30. The composition as claimed in claim 28, in which the biovector is selected from the amino alcohols of general formula (II)

31. The composition as claimed in claim 1, in which the X groups form a covalent bond with the biovector, of type —

CONH—

, —

COO—

, —

NHCO—

, —

OCO, —

NH—

CS—

NH—

, —

C—

S—

, —

N—

NH—

CO—

, —

CO—

NH—

N—

, —

CH₂—

NH—

, —

N—

CH₂—

, —

N—

CS—

N—

, —

CO—

CH₂—

S—

, —

N—

CO—

CH₂—

S—

, —

N—

CO—

CH₂—

CH₂—

S, —

CH═

NH—

NH—

, —

NH—

NH═

CH—

, —

CH═

N—

O—

or —

O—

N═

CH—

, and also the formulae below

32. The composition as claimed in claim 1, in which the particles complexed and coupled to the biovector(s) have an overall hydrodynamic diameter of between 5 nm and 200 nm.

33. The composition as claimed in claim 1, in which the concentration of the particles (p) in the composition is between 2 μ

mol L<sup>−

1</sup> and 4 mol L<sup>−

1</sup>, expressed as total number of moles of metal ions.

34. The composition as claimed in claim 1, comprising one or more pharmaceutically acceptable vehicle(s) and/or additive(s).

35. The composition as claimed in claim 1, which is sterile.

36. A process for the preparation of a composition as claimed in claim 1, said process comprising the successive steps consisting in:

(i) bringing an acid solution of acid magnetic particles (p) based on an iron compound into contact with compounds of formula (I) as defined in claim 1 in sufficient amount, and recovering the complexed particles obtained;

where appropriate,

ii) coupling all or some of the X groups of the compounds of formula (I) complexed at the surface of the magnetic particles (p) with biovectors.

37. The process as claimed in claim 36, in which the magnetic particles (p) used in step (i) are obtained according to a process comprising the steps consisting in:

a) preparing a colloidal solution of acid ferrofluid;

b) treating the solution obtained in step a) with a nitric acid solution;

c) isolating the flocculate obtained in step b); and

d) carrying out a peptization.

38. A contrast product for magnetic resonance imaging, comprising a composition as claimed in claim 1, combined with a suitably acceptable vehicle.

39. A method of therapeutic treatment, in which a composition comprising acid magnetic particles (p) coupled to at least one biovector as defined in claim 1, in combination with a pharmaceutically acceptable vehicle, is administered to a patient requiring such a treatment.

40. The method as claimed in claim 39, in which at least one biovector has pharmacological and/or cytotoxic properties.

41. The method as claimed in claim 40, in which the biovector is released under the action of a radiofrequency field in a targeted area.

42. The method as claimed in claim 39, in which at least one biovector is specific for a biological receptor.

43. The method as claimed in claim 42, also comprising the application of a radiofrequency field in the targeted area of the treated patient, by virtue of which the patient is subjected to hyperthermia of said targeted area.

44. The method as claimed in claim 39, in which the acid magnetic particles (p) comprise a radioactive iron isotope.

45. A method of diagnosis or of monitoring by medical magnetic resonance imaging, in which a composition as claimed in claim 1 comprising acid magnetic particles (p) is administered to a patient, which makes it possible to visualize an organ or a pathology in the patient by magnetic resonance.

46. The method as claimed in claim 45, for the diagnosis or monitoring of a pathology selected from cardiovascular diseases, cancers, and inflammatory and degenerative diseases.

47. A method for the in vitro detection and/or separation of cells, comprising:

i) bringing cells into contact with a composition as claimed in claim 1, comprising acid magnetic particles (p) coupled to at least one biovector capable of labeling the cells; and

ii) detecting and/or separating the labeled cells obtained.

48. The method as claimed in claim 47, in which the biovector is a ligand specific for a biological receptor expressed by the cells to be labeled.

49. A method for the diagnosis of pathologies related to cell dysfunction, comprising

i) labeling stem cells ex vivo from a patient according to the method of claim 27, and

ii) administering the labeled stem cells to said patient;

which makes it possible, under the application of a magnetic field, to follow the movement, location and survival of the exogenous cells by MRI visualization and thus to detect pathologies related to cell dysfunction.