Water soluble nitric oxide-releasing polyglucosamines and uses thereof
View Patent ↗The presently disclosed subject matter provides nitric oxide-releasing polysaccharides and oligosaccharides, in particular, polyglucosamines, and their use in biomedical and pharmaceutical applications. More particularly, in some embodiments, the presently disclosed subject matter provides nitric oxide-releasing polysaccharides and oligosaccharides that release nitric oxide in a controlled and targeted manner, thereby prolonging the therapeutic effects of nitric oxide and improving the specificity of nitric oxide delivery to targeted cells and/or tissues.
1. A polyglucosamine comprising,
at least one structural unit:
wherein,
Q is —(CR c R d ) v —;
wherein R c and R d , in each instance, are independently hydrogen or C 1-5 alkyl; and v is an integer from 2 to 6;
p is an integer from 1 to 10;
A is
wherein, L is S, O or N; and
G, in each instance, is independently, hydrogen, or is taken together with
L to form a nitric oxide donor or is absent;
X is hydrogen, C 1-5 alkyl or is taken together with N to form a nitric oxide donor;
B is absent or is selected from the group consisting of hydrogen, hydroxyl, C 1-5 alkyl, or —Y—Z, wherein Y is a spacer and Z is a polymer or a terminus;
wherein the polyglucosamine comprises at least one nitric oxide donor selected from the group consisting of a diazeniumdiolate, nitrosothiol, a nitrosamine, a hydroxyl nitrosamine, a hydroxyl amine, a hydroxyurea, and combination thereof; and
wherein G is taken together with L to form the at least one nitric oxide donor or X is taken together with N to form the at least one nitric oxide donor.
2. The polyglucosamine of claim 1 , wherein said at least one nitric oxide donor is a diazeniumdiolate.
3. The polyglucosamine of claim 1 , wherein B is hydrogen.
4. The polyglucosamine of claim 1 , wherein B is —Y—Z.
5. The polyglucosamine of claim 4 , wherein B is —Y—Z, wherein Z has the structure:
wherein j, in each instance, is an integer from 1 to 100.
6. The polyglucosamine of claim 4 , wherein Y has the structure:
wherein,
R p , R q , R s and R t , in each instance, are independently, hydrogen or hydroxyl; and
k is an integer from 1 to 20.
7. The polyglucosamine of claim 1 , wherein
B is —Y—Z, wherein Z has the structure:
wherein j, in each instance, is an integer from 1 to 100.
8. The polyglucosamine of claim 7 , wherein j is an integer from 1 to 50.
9. The polyglucosamine of claim 7 , wherein j is an integer from 1 to 15.
10. The polyglucosamine of claim 1 , wherein
A is
wherein G is hydrogen, or is taken together with N to form a nitric oxide donor or is absent; and
B is hydrogen.
11. The polyglucosamine of claim 10 , wherein
X is hydrogen or is taken together with N to form a diazeniumdiolate; and
A is
wherein G is hydrogen or is taken together with N to form a diazeniumdiolate.
12. The polyglucosamine of claim 1 , comprising the structural unit:
wherein,
m is an integer from 1 to 1,000, and
n is an integer from 1 to 1,000.
13. The polyglucosamine of claim 12 , wherein m and n are each independently selected from an integer of 1 to 50.
14. The polyglucosamine of claim 13 , wherein Y has the structure:
wherein,
R p , R q , R s and R t , in each instance, are independently, hydrogen or hydroxyl; and
k is an integer from 1 to 20.
15. The polyglucosamine of claim 12 , wherein m and n are each independently selected from an integer from 1 to 10.
16. The polyglucosamine of claim 12 , comprising the structural unit:
17. The polyglucosamine of claim 12 , wherein
B is —Y—Z, wherein Z has the structure:
wherein j, in each instance, is an integer from 1 to 100.
18. The polyglucosamine of claim 1 , wherein A is N.
19. The polyglucosamine of claim 1 , wherein A is S.
20. The polyglucosamine of claim 1 , wherein
R c and R d , in each instance, are independently hydrogen or methyl; and
v is 2.
21. The polyglucosamine of claim 1 , wherein said polyglucosamine is water soluble.
22. The polyglucosamine of claim 1 , wherein said polyglucosamine has a molecular weight from 100 to 20,000 g/mol.
23. The polyglucosamine of claim 1 , wherein G is taken together with L to form said at least one nitric oxide donor.
24. The polyglucosamine of claim 1 , wherein X is taken together with N to form said at least one nitric oxide donor.
25. The polyglucosamine of claim 24 , wherein said at least one nitric oxide donor is a diazeniumdiolate.
26. The polyglucosamine of claim 24 , wherein said at least one nitric oxide donor is a nitrosothiol.
27. The polyglucosamine of claim 1 , comprising the structural unit:
wherein,
m is an integer from 1 to 1,000, and
n is an integer from 1 to 1,000.
28. The polyglucosamine of claim 1 , comprising the structural unit:
wherein,
m is an integer from 1 to 1,000, and
n is an integer from 1 to 1,000.
29. A polyglucosamine comprising:
at least one structural unit:
wherein,
m is an integer from 1 to 1,000, and
n is an integer from 1 to 1,000.
30. The polyglucosamine of claim 29 , wherein m and n are each independently selected from an integer of 1 to 50.
31. A polyglucosamine comprising:
at least one structural unit:
wherein,
m is an integer from 1 to 1,000, and
n is an integer from 1 to 1,000.
32. The polyglucosamine of claim 31 , wherein m and n are each independently selected from an integer of 1 to 50.
33. A method of delivering nitric oxide to a subject, comprising:
administering an effective amount of said polyglucosamine of claim 1 to said subject.
34. A method of treating a disease state, comprising:
administering an effective amount of said polyglucosamine of claim 1 to a subject in need thereof, wherein said disease state is selected from the group consisting of a cancer, a cardiovascular disease, a microbial infection; platelet aggregation and platelet adhesion caused by the exposure of blood to a medical device; pathological conditions resulting from abnormal cell proliferation; transplantation rejections, autoimmune diseases, inflammation, vascular diseases; scar tissue; wound contraction, restenosis, pain, fever, gastrointestinal disorders, respiratory disorders, sexual dysfunctions, and sexually transmitted diseases.
35. The method of claim 34 , wherein said disease state is cystic fibrosis.
36. A pharmaceutical formulation comprising:
i. said polyglucosamine of claim 1 ; and
ii. a pharmacuetically acceptable carrier.
37. The pharmaceutical formulation of claim 36 , wherein said polyglucosamine is water-soluble.