Dendri-tac and their use as theranostics

Patent metadata

Field	Value
Publication number	US-2018126011-A1
Application number	US-201615571528-A
Country	US
Kind code	A1
Filing date	May 19, 2016
Priority date	May 19, 2015
Publication date	May 10, 2018
Grant date	—

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.

First claim

1 . Amphophilic 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 mono-, oligo- or polysaccharide residue, 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 1a) or 1b):

wherein:
W is F or a group selected from W 0 , Wj, W 2

W 0
RF is a C4-C0 perfluoroalkyl or a Cj-024 alkyl group,
RH is a Q-C24 alkyl group,
p is 0, 1, 2, 3 or 4;
q is 0, 1, 2, 3 or 4;
L is a linear or branched Ci-C 12 alkylene group, optionally interrupted by one or more -0-, —S—,
2 is C(=0)NH or NHC(=0),
R is a Ci˜C 6 alkyl group, and
e is at each occurrence independently selected from 0, 1, 2, 3 or 4.

2 . Dendrimer of claim 1 , wherein WL is a group selected from:

3 . Dendrimer of claim 1 , wherein each generation chain (n) branches vi follows:
is a group (a) or a group (b) as defined in claim 1 as:

wherein
Z is C(=0)NH or NHC(=0),
R is a Ci-C 6 alkyl group, and
e is at each occurrence independently selected from 0, 1, 2, 3 or 4.

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

5 . Dendrimer of claim 1 , having the following formula:

wherein:
W is R F or a group selected from:

Wo w, V¾ 3
RF being a C 4 -C 10 perfluoroalkyl or a Cj-C 2 4 alkyl group and RH being a C \ -C 2 4 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);
Ri, R 2 . R3 are H, or a group selected from (c) or (d):

provided that:
Ri, R 2 , R3 are the same and selected from either group (c) or (d) or one of Ri, R 2 , R3 is H, the two others being the same and selected from either group (c) or (d);
X is X 3 when j is 1 and X when j is 0;
X a is at each occurrence independently selected from —OC(=0)CH 2 —NH—, —OC(0)CH 2 -0-CH 2 ˜, -0(CH 2 ) r C(=0)-NH—, -0(CH 2 ) r C(=0)-0-CH 2 , OC(=0)NH—, —C(=0>, —NH—, and —OCH 2 —;
Y a is independently selected from:

Xb is

Y b is independently selected from:

V is

R4, R 7 are each independently selected from H, Cj-Ce alkyl and CHaO jo;
R 5 is selected from H and]-alkyl;
R 6 is a mono-, oligo-, polysaccharide or a cyclodextrin residue;
Rg, R9 are each independently a peptide residue;
Rio is H or a monosacchraide selected from glucose, galactose, mannose; i is 0 or 1;
j is 0 or 1;
e is 0, 1, 2, 3 or 4;
k is an integer iron 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 I to 6;

6 . Dendrimer which is selected from: 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 amphophilic 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 farther 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), photofrifl Π, hematoporphyrin monomethyi 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 PPFX derivatives of the following formula:

wherein
R x is a C 1 -C 14 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 amphophilic 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

Assignees

• Univ Davignon Et Des Pays Du Vaucluse
• Centre Nat Rech Scient

Inventors

• Desgranges Stéphane
• Urbach Wlodzimierz
• Somaglino Lucie
• Taulier Nicolas
• Pepin Christiane

Classifications

• A61K41/0028

  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 title

• A61K49/1806 Primary

  Suspensions, emulsions, colloids, dispersions · CPC title

• C08G83/008

  Supramolecular polymers · CPC title

• A61K49/0078

  microemulsion, nanoemulsion · CPC title

• C08G83/004

  After treatment of dendrimers · CPC title