Dendri-TAC and their use as theranostics

• US 10,286,091 B2
• Filed: 05/19/2016
• Issued: 05/14/2019
• Est. Priority Date: 05/19/2015
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Université d'Avignon
• Original Assignee: Centre National De La Recherche Scientifique, Université d'Avignon
• Inventors: Desgranges, Stephane, Urbach, Wlodzimierz, Somaglino, Lucie, Taulier, Nicolas, Pepin, Christiane
• Primary Examiner(s): Dickinson, Paul W
• Application Number:
  US15/571,528
• Publication Number:
  US 20180126011A1
• Time in Patent Office: 1,090 Days
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 41/0033 Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds ultrasound therapy per se A61N7/00
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• CPC Class Codes: A61K 49/0028 Oxazine dyes
• CPC Class Codes: A61K 49/0036 Porphyrins used in photodynamic therapy A61K41/0071 or A61K41/0076; used as targeting group or modifying agent for targeting a therapeutic compound A61K47/546
• CPC Class Codes: A61K 49/0078 microemulsion, nanoemulsion
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/226 Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
• CPC Class Codes: B01J 31/064 Dendrimers
• CPC Class Codes: C08G 83/003 Dendrimers
• CPC Class Codes: C08G 83/004 After treatment of dendrimers
• CPC Class Codes: C08G 83/008 Supramolecular polymers

Abstract

The present invention relates to novel amphiphilic dendrimers, hereafter denoted Dendri-TAC. The present invention also relates to perfluorocarbon nanoemulsions stabilized by these amphiphilic dendrimers and their uses for in vivo diagnostic and/or for therapy, notably as theranostic tools, for detection and/or treatment of cancer.

Claims

1. An amphiphilic dendrimer of generation n comprising:

an hydrophobic central core of valence 2 or 3;

generation chains attached to the central core and branching around the core; and

an hydrophilic terminal group at the end of each generation chain;

wherein,

n is an integer from 0 to 12;

the hydrophilic terminal group comprises;

a cyclodextrin residue,

a polyethylene glycol (PEG) residue,

a peptide residue,

a tris(hydroxymethyl)aminoethane (Tris), or

a 2-amino-2-methylpropane-1,3-diol;

the central core being a group of formula (Ia) or (Ib);

2. The dendrimer of claim 1, wherein WL is a group selected from the group consisting of:

3. The dendrimer of claim 1, wherein each generation chain (n) branches via a group (a) or a group (b) as defined in claim 1 as follows:

4. The dendrimer of claim 1, wherein the terminal group comprises the following hydrophilic moieties:

5. The dendrimer of claim 1, having the following formula:

6. A dendrimer which is selected from the group consisting of:

7. A nanoemulsion comprising:

as a discontinuous phase, a perfluorocarbon compound,

as a continuous phase, an aqueous phase,

an amphiphilic dendrimer as defined in claim 1 as a surfactant,

optionally a biocompatible hydrocarbon oil.

8. The nanoemulsion of claim 7, wherein the discontinuous phase is loaded with solubilized oxygen.

9. The nanoemulsion of claim 7, wherein the discontinuous phase further comprises a sonosensitive and/or photosensitive agent and/or an active ingredient.

10. The nanoemulsion of claim 7, wherein the discontinuous phase further comprises a sonosensitive and/or photosensitive agent and/or an active ingredient, said nanoemulsion further comprising a biocompatible hydrocarbon oil.

11. The nanoemulsion of claim 10, wherein the sonosensitive and/or photosensitive agent is selected from protoporphyrin IX (PpIX), hematoporphyrin (Hp), photofrin II, hematoporphyrin monomethyl ether (HMME), ATX-70, chlorin e6, chlorin family (dihydroporphyrin), bacteriochlorin family (tetrahydroporphyrin), ATX-S10, sinoporphyrin sodium (called DVDMS) or a chlorophyll-derived porphyrin analogue, and PPIX derivatives of the following formula:

12. A method of diagnosis or treatment comprising a step of administration to a patient in need thereof an effective amount of the nanoemulsion of claim 7.

13. The method of claim 12, in tumor imaging.

14. The method of claim 13, wherein the tumor imaging is selected from contrast echography, near-infrared fluorescence, photoacoustic imaging and Magnetic Resonance Imaging (MRI), in particular from ultrasound echography, and fluorine Nuclear Magnetic Resonance.

15. The method of claim 12, in the treatment of cancer.

16. The method of claim 15, in sonodynamic or photodynamic therapy.

17. The method of claim 12, wherein the terminal group of the dendrimer comprises or is attached to a targeting ligand.

18. The method of claim 17, wherein the targeting ligand is a RGD peptide.

19. A nanoparticle comprising:

a core containing a perfluorocarbon compound, said core being optionally surrounded by a layer of biocompatible hydrocarbon oil,

a shell composed of amphiphilic dendrimers according to claim 1.

20. A process of preparation of a nanoemulsion comprising:

as a discontinuous phase, a perfluorocarbon compound,

as a continuous phase, an aqueous phase,

an amphiphilic dendrimer according to claim 1,

optionally a biocompatible hydrocarbon oil,

said process comprising;

a step of emulsifying a system comprising;

an aqueous phase comprising an amphiphilic dendrimer according to claim 1,

a perfluorocarbon compound,

optionally a biocompatible hydrocarbon oil,

to obtain said nanoemulsion.

21. Process according to claim 20 further comprising a step of storage of the obtained nanoemulsion.

22. Process according to claim 21 further comprising a step of storage of the obtained nanoemulsion by freezing said nanoemulsion to obtain a frozen nanoemulsion.

23. Process according to claim 22 further comprising a step of obtaining a ready-to-use nanoemulsion from the frozen nanoemulsion by defrosting the frozen nanoemulsion.

24. Process according to claim 21 further comprising a step of storage of the obtained nanoemulsion by freeze-drying said nanoemulsion to obtain a lyophilized nanoemulsion.

25. Process according to claim 24 further comprising a step of obtaining a ready-to-use nanoemulsion from the lyophilized nanoemulsion by resuspending the lyophilized nanoemulsion in water.