Dendri-TAC and their use as theranostics

Patent metadata

Field	Value
Publication number	US-10286091-B2
Application number	US-201615571528-A
Country	US
Kind code	B2
Filing date	May 19, 2016
Priority date	May 19, 2015
Publication date	May 14, 2019
Grant date	May 14, 2019

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

The invention claimed is:

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

Assignees

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

Inventors

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

Classifications

• A61K49/0036

  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 title

• C08G83/008

  Supramolecular polymers · CPC title

• A61K47/6907

  the form being a microemulsion, nanoemulsion or micelle · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• 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