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:
and optionally, at least one structural unit:
wherein,
i. R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , are each hydrogen;
ii. is a single bond;
iii. Q is —(CR c R d ) v —; wherein R c and R d are hydrogen and v is 2;
iv. p is an integer from 1 to 10;
v. A is
wherein, L is N and G is hydrogen;
vi. X is taken together with N to form a nitric oxide donor;
vii. B is hydrogen; and
viii. D is —NR a R b , wherein R a and R b are hydrogen.
2. The polyglucosamine of claim 1 , wherein p is 1.
3. The polyglucosamine of claim 1 , wherein the nitric oxide donor taken together with the atom on the polyglucosamine to which it is bound is selected from the group consisting of a diazeniumdiolate, nitrosothiol, a nitrosamine, a hydroxyl nitrosamine, a hydroxyl amine, a hydroxyurea, and combination thereof.
4. The polyglucosamine of claim 1 , wherein the nitric oxide donor is diazeniumdiolate.
5. The polyglucosamine of claim 1 , wherein the polyglucosamine is water soluble.
6. The polyglucosamine of claim 1 , wherein the polyglucosamine is water soluble such that >50 mg of the polyglucosamine dissolves per mL of water.
7. The polyglucosamine of claim 1 , wherein the polyglucosamine is water soluble such that >75 mg of the polyglucosamine dissolves per mL of water.
8. The polyglucosamine of claim 1 , wherein the polyglucosamine is water soluble such that >100 mg of the polyglucosamine dissolves per mL of water.
9. The polyglucosamine of claim 1 , wherein the viscosity average molecular weight (M v ) as determined by the equation [η]=1.81×10 −3 M v 0.93 is between about 2000 and about 11000 g/mol.
10. The polyglucosamine of claim 1 , wherein the viscosity average molecular weight (My) as determined by the equation [η]=1.81×10 −3 M v 0.93 is between about 3000 and about 6000 g/mol.
11. The polyglucosamine of claim 1 , wherein the elemental composition is:
between about 40% and about 50% C;
between about 6% and about 9% H; and
between about 3% and about 11% N.
12. The polyglucosamine of claim 1 , wherein the elemental composition is:
between about 42% and about 51% C;
between about 6% and about 9% H; and
between about 3% and about 11% N.
13. The polyglucosamine of claim 1 , wherein the polyglucosamine includes greater than about 0.3 μmol/mg of releasable nitric oxide.
14. The polyglucosamine of claim 1 , wherein the polyglucosamine includes greater than about 0.8 μmol/mg of releasable nitric oxide.
15. A method of delivering nitric oxide to a subject, comprising:
administering an effective amount of the polyglucosamine of claim 1 to the subject.
16. A method of treating a disease state, comprising:
administering an effective amount of the polyglucosamine of claim 1 to a subject in need thereof, wherein the 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.
17. The method of claim 16 , wherein said disease state is cystic fibrosis.
18. A pharmaceutical formulation comprising:
the polyglucosamine of claim 1 ; and
a pharmaceutically acceptable carrier.