Hyaluronic acid conjugates and uses thereof

1. A graft polymer of a hyaluronic acid polymer and a N-isopropylacrylamide based polymer wherein the hyaluronic acid polymer and the N-isopropylacrylamide based are conjugated through at least one linker L of Formula (II):

wherein one of Ra and Rb is covalently linked to the N-isopropylacrylamide based polymer and one of Ra and Rb is covalently linked to the hyaluronic acid polymer and when Ra or Rb is covalently linked to the N-isopropylacrylamide based polymer, it is equal to R 1 and when Ra or Rb is covalently linked to the hyaluronic acid polymer, it is equal to R 3 , wherein R 1 is a group selected from (CH 2 ) x —NH(CH 2 ) y —S—, —(CH 2 ) x —NH—O—C(O)—(CH 2 ) y —S—, —(CH 2 ) x —NH—(CH 2 ) y —C(O)—NH—(CH 2 ) z —S—, —(CH 2 ) x —O—C(O)—CR 7 R 8 —, —C(O)—(CH 2 ) x —C(O)—NH—(CH 2 ) z —S and an optionally substituted polyethylene chain wherein R 7 and R 8 are optionally substituted C 1 -C 6 alkyl; R 3 is a group -E-G-L 1 - wherein E is either absent or selected from —C(O)—NR 9 —, —C(O)—O— and —C(O)—, G is linker group selected from optionally substituted C 1 -C 20 alkyl, optionally substituted polyethylene glycol (PEG) chain, optionally substituted acylamino C 1 -C 6 alkyl, optionally substituted acyl C 1 -C 6 alkyl, optionally substituted aminocarbonyl C 1 -C 6 alkyl and optionally substituted C 1 -C 6 alkoxy and L 1 is selected from —NR 10 C(O)—, —C(O)—NR 10 —, —C(O)—O— and —C(O)— wherein R 9 and R 10 are independently selected from H and optionally substituted C 1 -C 6 alkyl; A is an optionally substituted C 5 -C 10 -cycloalkyl, or optionally substituted heterocycloalkyl ring wherein R 5 represents one or more substituent(s) independently selected from H, optionally substituted alkoxy and optionally substituted C 1 -C 6 alkyl; x, y and z are integers independently selected from 1 to 20 or any pharmaceutically acceptable salts thereof.

2. The graft polymer according to claim 1 of Formula (I):

wherein M is a group selected from a moiety of Formula (M1) and of Formula (M2):

R 2 is a group —B—(CH 2 ) i -D, wherein B is either absent or selected from —S—C(S)—S— and —S—; D is a group selected from optionally substituted C 1 -C 15 alkyl, optionally substituted alkoxycarbonyl C 1 -C 4 alkyl, optionally substituted amino C 1 -C 4 alkyl, optionally substituted aminocarbonyl C 1 -C 6 alkyl, —COOH and —NH 2 ; p is an integer independently selected from 1 to 500; i is an integer independently selected from 0 to 500; R 6 is a group selected from —COOH and R 3 , depending on the degree of substitution; L is a linker of Formula (II) as defined in claim 1 and n is an integer selected from 1 to 7,000 or any pharmaceutically acceptable salts thereof.

3. The graft polymer according to claim 1 , having a Formula (Ia):

or any pharmaceutically acceptable salts thereof wherein L is a linker as defined in claim 1 ; R 2 is a group —B—(CH 2 ) i -D, wherein B is either absent or selected from —S—C(S)—S— and —S—; R 6 is a group selected from —COOH and R 3 , depending on the degree of substitution and p is an integer independently selected from 1 to 500.

4. The graft polymer according to claim 1 , wherein the linker L is linked to the HA polymer of the graft polymer through its R b substituent.

5. The graft polymer according to claim 1 , wherein the linker L is linked to the HA polymer of the graft polymer through its R a substituent.

6. The graft polymer according to claim 1 , wherein x is from 2 to 10.

7. The graft polymer according to claim 1 , wherein B is absent or —S—C(S)—S—.

8. The graft polymer according to claim 1 , wherein L is a group according to Formula (II′):

wherein R 11 and R 12 represent one or more substituent independently selected from H, optionally substituted alkoxy and optionally substituted C 1 -C 4 alkyl; R a and R b are as described in claim 1 .

9. The graft polymer according to claim 1 , wherein L is a group according to Formulae (II) having a formula selected from Formula (II″) and (II′″):

wherein Q is absent or a group of the following formula: —NH—C(O)—(CH 2 —CH 2 —O) 1-4 —CH 2 —CH 2 —; G 1 is a PEG, in particular (CH 2 —CH 2 —O) 1-4 — and R 11 and R 12 represent one or more substituent independently selected from H, optionally substituted alkoxy and optionally substituted C 1 -C 4 alkyl.

10. The graft polymer according to claim 1 , wherein said graft polymer is selected from the following group:

having a substitution degree between about 0.5 and 50 or any pharmaceutically acceptable salts thereof.

11. A method for the preparation of a graft polymer of a hyaluronic acid polymer and N-isopropylacrylamide based polymer wherein the hyaluronic acid polymer and the N-isopropylacrylamide based are conjugated by at least one linker L of Formula (II)

wherein A, Ra, Rb and R5 are as defined in claim 1 ,

comprising the steps of:

(a) providing an HA polymer having at least one carboxylic acid group which is conjugated to at least one first functional group capable of participating in a “click chemistry” reaction;

(b) providing a N-isopropylacrylamide based polymer having at least one-second complementary functional group capable of participating in a “click chemistry” reaction with the first functional group wherein said one of the functional groups is an azide moiety and the other functional group is an alkyne-bearing precursor of the said linker L;

(c) reacting the at least one first functional group of the HA polysaccharide with the at least one-second complementary functional group of the N-isopropylacrylamide based polymer via a “click chemistry” reaction to obtain a graft polymer composition of the invention; and

(d) isolating the graft polymer composition.

12. A composition comprising at least one graft polymer according to claim 1 and at least one carrier.

13. The composition according to claim 12 , wherein said composition is a hydrogel or nanoparticle composition.

14. The composition according to claim 12 , wherein said composition is a cell or tissue culture medium further comprising cell or tissue nutrients.

15. The composition according to claim 12 , wherein said composition is a reconstruction tissue.

16. The composition according to claim 12 , wherein said composition is a cosmetic composition and the said carrier is a cosmetically acceptable carrier.

17. A soft tissue filler comprising at least one graft polymer according to a graft polymer according to claim 1 .

18. A method for the preparation of a delivery system of an active principle, said method comprising the steps of:

a) Providing a graft polymer or hydrogel according to claim 1 in gel state;

b) Providing an active principle to be delivered;

c) Mixing the said graft polymer composition or hydrogel with the said active principle;

d) Optionally inducing formation of nanoparticles by increasing the temperature to the mixture; and

e) Collecting the obtained composition, hydrogel or nanoparticles loaded with the active principle.

19. A method of preventing, treating or ameliorating a medical disorder selected from joint pathologies, articular diseases, eye pathologies, skin defects or injuries, urological tissue bulking and any tissue degeneration, a tumor or a vascular malformation in a subject, said method comprising administering to a subject in need thereof an effective amount of at least one HA graft polymer according to claim 1 or a pharmaceutical formulation thereof.

20. The composition according to claim 12 , wherein the carrier is a pharmaceutically acceptable carrier.

21. A method of preparing a cell or tissue culture medium comprising mixing at least one HA graft polymer according to claim 1 with cell or tissue culture medium.

22. A method of preparing a material for tissue engineering comprising mixing at least one HA graft polymer according to claim 1 with a tissue engineering material.

23. The method according to claim 22 , wherein the tissue engineering material is bone, cartilage, epidermal material or cells.

24. A method of preparing a composition comprising mixing at least one HA graft polymer according to claim 1 with a carrier.