Dendri-TAC and their use as theranostics

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):

wherein:

W is R F or a group selected from the group consisting of W 0 , W 1 , W 2 and W 3 :

R F is a C 4 -C 10 perfluoroalkyl or a C 1 -C 24 alkyl group,

R H is a C 1 -C 24 alkyl group,

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3 or 4;

L is a linear or branched C 1 -C 12 alkylene group, optionally interrupted by one or more —O—, —S—,

Z is C(═O)NH or NHC(═O),

R is a C 1 -C 6 alkyl group, and

e is at each occurrence independently 0, 1, 2, 3 or 4.

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:

wherein

Z is C(═O)NH or NHC(═O),

R is a C 1 -C 6 alkyl group, and

e is at each occurrence independently 0, 1, 2, 3 or 4.

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

wherein,

R 4 is H, C 1 -C 6 alkyl, or CH 2 OR 10 ;

R 5 is H, or C 1 -C 6 alkyl;

R 10 is H;

w is an integer from 1 to 20; and

x is an integer from 1 to 30.

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

wherein:

W is R F or a group selected from the group consisting of:

R F being a C 4 -C 10 perfluoroalkyl or a C 1 -C 24 alkyl group and R H being a C 1 -C 24 alkyl group,

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3 or 4;

Z is (CO)NH or NH(CO);

R 1 , R 2 , R 3 are H, or a group selected from the group consisting of (c) and (d):

provided that:

R 1 , R 2 , R 3 are the same and either group (c) or (d) or

one of R 1 , R 2 , R 3 is H, the two others being the same and either group (c) or (d);

X is X a when j is 1 and X b when j is 0;

X a is at each occurrence independently —OC(═O)CH 2 —NH—, —OC(═O)CH 2 —O—CH 2 —, —O(CH 2 ) r C(═O)—NH—, —O(CH 2 ) r C(═O)—O—CH 2 , OC(═O)NH—, —C(═O)—, —NH—, or —OCH 2 —;

Y a is independently selected from the group consisting of:

X b is

Y b is independently selected from the group consisting of:

V is

R 4 , R 7 are each independently H, C 1 -C 6 alkyl or CH 2 OR 10 ;

R 5 is H or C 1 -C 6 alkyl;

R 6 is a cyclodextrin residue;

R 8 , R 9 are each independently a peptide residue;

R 10 is H;

i is 0 or 1;

j is 0 or 1;

e is 0, 1, 2, 3 or 4;

k is an integer from 1 to 12, preferably 1, 2, 3, 4, or 5;

r is an integer from 1 to 10;

u is 0, 1, 2, 3 or 4;

v is 1, 2, or 3;

w is an integer from 1 to 20, preferably from 1 to 10;

x is an integer from 1 to 30, preferably from 5 to 15;

y, z are each independently an integer from 1 to 6.

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

wherein x and w are as defined in claim 1 .

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:

wherein

R x is a C 1 -C 10 perfluoroalkyl or a C 1 -C 24 alkyl group,

y is 0, 1, 2, 3 or 4,

z is 1 to 200.

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.