HYDROPHOBICALLY-MODIFIED HYALURONAN AND METHODS OF MAKING AND USING THEREOF
Described herein are modified hyaluronans or the pharmaceutically-acceptable salt or ester thereof, wherein the modified hyaluronan comprises at least one hydrophobic polypeptide covalently bonded to hyaluronan. The modified hyaluronans can be used as viscosupplements in a number of medical applications. The modified hyaluronans can also be used in several biological and medical applications. Methods for preparing the modified hyaluronans are also provided herein.
1 . A modified hyaluronan or the pharmaceutically-acceptable salt or ester thereof, wherein the modified hyaluronan comprises at least one hydrophobic polypeptide covalently bonded to hyaluronan.
2 . The modified hyaluronan of claim 1 , wherein the hyaluronan has a molecular weight of 50,000 to 10,000,000.
3 . The modified hyaluronan of claim 1 , wherein the hydrophobic polypeptide has from 5 to 20 amino acid residues.
4 . The modified hyaluronan of claim 1 , wherein the hydrophobic polypeptide has a molecular weight from 600 to 3,000.
5 . The modified hyaluronan of claim 1 , wherein the hydrophobic polypeptide comprises diblock polypeptide comprising a hydrophilic block and a hydrophobic block, wherein the hydrophilic block is covalently attached to hyaluronan.
6 . The modified hyaluronan of claim 1 , wherein the hydrophobic polypeptide is isotactic poly(leucine), atactic poly(leucine), or a combination thereof.
7 . The modified hyaluronan of claim 1 , wherein the modified hyaluronan comprises a residue of formula I
wherein
Z is a residue of hyaluronan;
L is a linker; and
Y is a residue of a hydrophobic polypeptide.
8 . The modified hyaluronan of claim 1 , wherein the modified hyaluronan comprises a residue of formula II
wherein
Z is a residue of hyaluronan;
R 1 is hydrogen or methyl; and
Y is a residue of a hydrophobic polypeptide.
9 . The modified hyaluronan of claim 1 , wherein R 1 is hydrogen and Y is poly(leucine).
10 . The modified hyaluronan of claim 1 , wherein the modified hyaluronan has a grafting ratio of 1% of the HA repeat units to 10% of the HA repeat units.
11 . The modified hyaluronan of claim 1 , wherein the modified hyaluronan is an extrudable composition.
12 . The modified hyaluronan of claim 1 , wherein the hydrophobic polypeptide comprises a targeting compound covalently bonded to the polypeptide.
13 . A modified hyaluronan produced by the process comprising
a. reacting hyaluronan with a linker to produce a covalent bond between the linker and hyaluronan, wherein the linker possesses at least one group capable of reacting with an amino acid residue in a hydrophobic polypeptide to produce a covalent bond between the linker and the hydrophobic polypeptide; and
b. reacting the hyaluronan produced in step (a) with the hydrophobic polypeptide.
14 . The modified hyaluronan of claim 13 , wherein the linker possesses at least one group capable of undergoing a Michael addition with the hydrophobic polypeptide.
15 . The modified hyaluronan of claim 13 , wherein the linker comprises an acrylate or methacrylate.
16 . The modified hyaluronan of claim 13 , wherein the linker is acrylic acid, acrylic anhydride, or acrylolchloride.
17 . A pharmaceutical composition comprising the modified hyaluronan in any of claim 1 .
18 . (canceled)
19 . A method for treating or preventing arthritis in a subject comprising administering the modified hyaluronan in any of claim 1 to the subject.
20 . The method of claim 19 , wherein the modified hyaluronan is injected into the joint of a subject.
21 . A method for reducing friction in a joint of a subject, the method comprising injecting the modified hyaluronan in any of claim 1 into the joint.
22 . A method for increasing the viscosity of synovial fluid in a joint of a subject, the method comprising contacting the synovial fluid with the modified hyaluronan in any of claim 1 .
23 . A method for the treatment or prevention of intervertebral disc degeneration, the method comprising administering the modified hyaluronan in any of claim 1 into an intervertebral disc.
24 . A method for minimizing an imperfection in a subject's skin, the method comprising injecting the modified hyaluronan in any of claim 1 in the skin of the subject at or near the imperfection.
25 . The method of claim 24 , wherein the imperfection is a wrinkle, a skin fold, a scar, atrophied skin, and sunken skin.
26 . A method for improving wound healing in a subject in need of such improvement, comprising contacting the wound of the subject with the modified hyaluronan in any of claim 1 .
27 . A method for delivering at least one pharmaceutically-acceptable compound to a subject in need of such delivery, comprising administering to the subject the modified hyaluronan in any of claim 1 .
28 . A method for growing tissues, comprising contacting precursor cells with the modified hyaluronan in any claim 1 .