Tunable nitric oxide-releasing macromolecules having multiple nitric oxide donor structures
View Patent ↗Provided here are nitric oxide-releasing compounds that include at least two different NO donor functional groups of the same class. In some embodiments, such nitric oxide-releasing compounds are macromolecules such as dendrimer and co-condensed silica. Pharmaceutical compositions, wound dressings, kits and methods of treatments are also provided herein.
1. A nitric oxide-releasing macromolecule comprising
at least two different NO donor structures of the same class,
wherein the at least two different NO donor structures have the same mechanism for release of NO and are different in chemical structure, and
wherein the at least two different NO donor structures are diazeniumdiolate donor structures and have different nitric oxide release kinetics.
2. The nitric oxide-releasing macromolecule of claim 1 , wherein at least one of the diazeniumdiolate donor structures has the formula —R—N(NONO − X + )—R′, wherein R is a divalent organic functional group, R′ is a monovalent organic functional group, and X + is a monovalent cation,
optionally wherein R is selected from alkylene or arylalkylene; R′ is selected from alkyl, substituted alkyl, alkylnitrile, aryl, substituted alkyl, alkylaryl, polyether and alkylamine; and X + is selected from Na + and K + .
3. The nitric oxide-releasing macromolecule of claim 1 , wherein at least one diazeniumdiolate donor structure comprises the structure:
wherein R is —CN, —COO(CH 2 CH 2 O) 6-12 H, —CH 3 , —CH 2 CH 3 , -Ph, —C 6 H 12 CH═CH 2 ; Z is —H or —OH; and X is Na + or K + .
4. The nitric oxide-releasing macromolecule of claim 1 , wherein the nitric oxide-releasing macromolecule comprises a dendrimer or co-condensed silica.
5. The nitric oxide-releasing macromolecule of claim 4 , wherein at least one of the diazeniumdiolate donor structures has a NO release half life in a range from 30 seconds to 10 minutes and at least one diazeniumdiolate donor structure has a NO release half life of greater than 60 minutes, as determined in aqueous buffer at pH 7.4 and 37° C.
6. The nitric oxide-releasing macromolecule of claim 4 , wherein at least one of the diazeniumdiolate donor structures has a NO release half life in a range from 30 seconds to 10 minutes and at least one diazeniumdiolate donor structure has a NO release half life greater than 10 minutes but less or equal to 60 minutes, as determined in aqueous buffer at pH 7.4 and 37° C.
7. The nitric oxide-releasing macromolecule of claim 4 , wherein at least one of the diazeniumdiolate donor structures has a NO release half life of more than 10 minutes but less or equal to 60 minutes and at least one diazeniumdiolate donor structure has a NO release half life greater than 60 minutes, as determined in aqueous buffer at pH 7.4 and 37° C.
8. The nitric oxide-releasing macromolecule of claim 4 , wherein at least one of the diazeniumdiolate donor structures has a maximum flux of NO in a range from 2000 ppb NO/mg to 20,000 ppb NO/mg and a half life in a range from 0.1 to 1 hour, and at least one diazeniumdiolate donor structure has a maximum flux of NO in a range from 100 ppb NO/mg to 2000 pp NO/mg and a half life in a range from 1 hour to 5 hours, as determined in aqueous buffer at pH 7.4 and 37° C.
9. The nitric oxide-releasing macromolecule of claim 5 , wherein the nitric oxide-releasing macromolecule comprises a dendrimer and at least one of the diazeniumdiolate donor structures comprises the structure:
wherein R is —CN, —COO(CH 2 CH 2 O) 6-12 H, —CH 3 , —CH 2 CH 3 , -Ph, —C 6 H 12 CH═CH 2 ; Z is —H or —OH; and X is Na + or K + .
10. The nitric oxide-releasing macromolecule of claim 4 , wherein the nitric oxide-releasing compound comprises co-condensed silica and at least one diazeniumdiolate donor structure comprises
wherein n is 1-5 and X is Na + or K + .
11. The nitric oxide-releasing macromolecule of claim 1 , wherein the macromolecule is present as particles having a mean particle size of less than 10 μm.
12. A pharmaceutical composition comprising the nitric oxide-releasing macromolecule of claim 1 , at least one excipient and, optionally, at least one additional therapeutic agent.
13. A kit comprising at least two pharmaceutical compositions of claim claim 12 .
14. A wound dressing comprising a polymer matrix and the NO releasing macromolecule of claim 1 .
15. A kit comprising at least two wound dressings of claim 14 .
16. A method of treating a dermatological condition, comprising topically administering the NO releasing macromolecule of claim 1 in an amount effective to actively promote healing of a wound associated with the dermatological condition.
17. The method of claim 16 , wherein the dermatological condition comprises at least one of a wound, microbial infection and inflammation.
18. The method of claim 16 , wherein the dermatological condition comprises acne.