Water soluble nitric oxide-releasing polyglucosamines and uses thereof

Patent metadata

Field	Value
Publication number	US-9850322-B2
Application number	US-201314421525-A
Country	US
Kind code	B2
Filing date	Aug 16, 2013
Priority date	Aug 17, 2012
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

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.

First claim

What is claimed is:

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 rejecti

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Schoenfisch Mark
• Lu Yuan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title