Nitric oxide-releasing alginates as biodegradable antibacterial scaffolds and methods pertaining thereto

Patent metadata

Field	Value
Publication number	US-11072668-B2
Application number	US-201816475615-A
Country	US
Kind code	B2
Filing date	Jan 3, 2018
Priority date	Jan 3, 2017
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

Large molecular weight alginates which are covalently modified to store and release nitric oxide, as well as methods of making and use thereof, are disclosed herein. The covalently modified alginates may be tailored to release nitric oxide in a controlled manner and are useful for eradication of both planktonic and biofilm-based bacteria.

First claim

What is claimed is:

1. A functionalized alginate comprising, one or more covalently modified monomers of Formula I

and optionally, one or more monomers of Formula II

wherein,
R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1-5 alkyl(C═O)—, and C 1-5 alkyl;
R 3 is hydrogen or C 1-5 alkyl;
R 4 is, in each instance, hydrogen or C 1-5 alkyl;
Q is —(CR a R b ) v —;
wherein R a and R b are independently hydrogen or C 1-5 alkyl; and v is an integer from 2 to 6;
A is

wherein, L is S, O, or N; and
G, in each instance, is hydrogen, is taken together with L to form a nitric oxide donor, or is absent;
wherein said nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl amine, a hydroxyurea, a nitrosothiol, a hydroxyl nitrosamine, and a combination thereof;

p is an integer from 1 to 10;
B is selected from the group consisting of hydrogen, —Y—Z, and C 1-5 alkyl, wherein said C 1-5 alkyl is optionally substituted with amino, hydroxyl, nitrile, CO 2 H, mono(C 1-6 )alkylamino-, di(C 1-6 )alkylamino-, —(CO)NR c R d or —NR c (CO)R d ,
wherein R c and R d are each independently selected from the group consisting of hydrogen and C 1-6 alkyl,
wherein Y has a structure of:

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; and
Z has a structure of:

wherein j, in each instance, is an integer from 1 to 100; and
wherein the functionalized alginate comprises at least one monomer of Formula I containing said nitric oxide donor.

2. The functionalized alginate of claim 1 , wherein said functionalized alginate has a total releasable nitric oxide storage in a range of 0.1-1.0 μmol of nitric oxide per milligram of the functionalized alginate.

3. A method for preparing the functionalized alginate of claim 1 , the method comprising:
i. contacting an amine of Formula III

with an alginate in the presence of a peptide coupling reagent, wherein,
R 4 , Q, A, B and p are as described above, wherein a covalently modified monomer of Formula I is prepared

wherein,
R 1 , R 2 , R 4 , Q, A, B and p are as described above; and
ii. contacting the alginate containing the covalently modified monomer of Formula I

with a nitric oxide source, wherein,
R 1 , R 2 , R 4 , Q, A, B and p are as described above, wherein the functionalized alginate of claim 1 is prepared.

4. A pharmaceutical formulation comprising:
i. said functionalized alginate of claim 1 ; and
ii. a pharmaceutically acceptable excipient.

5. The functionalized alginate of claim 1 , wherein L is N, and wherein said nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl amine, a hydroxyurea, and a combination thereof.

6. The functionalized alginate of claim 5 , wherein said functionalized alginate has a total releasable nitric oxide storage in a range of 0.1-1.0 μmol of nitric oxide per milligram of the functionalized alginate.

7. A pharmaceutical formulation comprising:
i. said functionalized alginate of claim 5 ; and
ii. a pharmaceutically acceptable excipient.

8. The functionalized alginate of claim 5 , wherein said nitric oxide donor is a diazeniumdiolate.

9. The functionalized alginate of claim 5 , wherein said nitric oxide donor is a nitrosamine.

10. The functionalized alginate of claim 5 , wherein said nitric oxide donor is a hydroxyl amine.

11. The functionalized alginate of claim 5 , wherein said nitric oxide donor is a hydroxyurea.

12. The functionalized alginate of claim 1 , wherein one or more monomers of Formula II are present.

13. The functionalized alginate of claim 5 , wherein one or more monomers of Formula II are present.

14. The functionalized alginate of claim 5 , wherein R 1 and R 2 are hydrogen or C 1-5 alkyl; and R 3 is hydrogen.

15. The functionalized alginate of claim 14 , wherein R 1 , R 2 , R 3 , and R 4 are hydrogen.

16. The functionalized alginate of claim 5 , wherein v is 2 or 3; L is N; and p is an integer from 1 to 3.

17. The functionalized alginate of claim 16 , wherein B is -Y-Z.

18. The functionalized alginate of claim 17 , wherein Y has the structure:

19. The functionalized alginate of claim 17 , wherein Z has the structure:

20. The functionalized alginate of claim 16 , wherein B is selected from the group consisting of hydrogen and C 1-5 alkyl, wherein said C 1-5 alkyl is optionally substituted with amino, hydroxyl, nitrile, CO 2 H, mono(C 1-6 )alkylamino-, di(C 1-6 )alkylamino-, —(CO)NR c R d or —NR c (CO)R d , and wherein R c and R d are each independently selected from the group consisting of hydrogen and C 1-6 alkyl.

21. A method for preparing the functionalized alginate of claim 5 , the method comprising:
i. contacting an amine of Formula III

with an alginate in the presence of a peptide coupling reagent, wherein,
R 4 , Q, A, B and p are as described above, wherein a covalently modified monomer of Formula I is prepared

wherein,
R 1 , R 2 , R 4 , Q, A, B and p are as described above; and
ii. contacting the alginate containing the covalently modified monomer of Formula I

with a nitric oxide source, wherein,
R 1 , R 2 , R 4 , Q, A, B and p are as described above, wherein the functionalized alginate of claim 5 is prepared.

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Schoenfisch Mark H
• Ahonen Mona Jasmine R
• Suchyta Dakota J
• Rouillard Kaitlyn Rose

Classifications

• C08L1/286

  substituted with acid radicals, e.g. carboxymethyl cellulose [CMC] (C08L1/282 takes precedence) · CPC title

• A61K47/61 Primary

  the organic macromolecular compound being a polysaccharide or a derivative thereof · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title