Zwitterionic crosslinkers, hydrogels comprising zwitterionic crosslinkers, and methods for making and using

1 . A crosslinker, having a Formula I

(Polymerizing Group 1) s -(Amino Acid) u -(Polymerizing Group 2) y   Formula I,

where:

polymerizing group 1 and polymerizing group 2 independently are provided by reaction with an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate;

each of s and y independently are from 1 to 10;

each amino acid independently is any naturally occurring amino acid, any non-naturally occurring amino acid, any combination thereof; and

u is 2 to 100.

2 . The crosslinker according to claim 1 , wherein the crosslinker is zwitterionic between a pH of from 2.5 to 10.

3 . The crosslinker according to claim 1 , wherein each amino acid is a naturally occurring amino acid selected to provide zwitterionic functional groups at a pH of from 2.5 to 10.

4 . The crosslinker according to claim 1 , wherein s and y are 1 and u is 2 to 10.

5 . The crosslinker according to claim 1 , wherein polymerizing group 1 and polymerizing group 2 independently are provided by reaction with an alkyl acrylate, alkyl acrylamide, alkyl acrylonitrile, or (hydroxyalkyl) acrylate.

6 . The crosslinker according to claim 1 , wherein polymerizing group 1 and polymerizing group 2 independently are provided by reaction with a methacrylate, ethylacrylate, propylacrylate, methacrylamide, ethylacrylamide, propylacrylamide, methacrylonitrile, ethylacrylonitrile, propylacrolynitrile, or (hydroxyethyl) methacrylate.

7 . The crosslinker according to claim 1 , where u is 2 to 10, and each amino acid independently is selected from serine, lysine, aspartic acid, glutamic acid, arginine, histidine, cysteine, threonine, or tyrosine.

8 . The crosslinker according to claim 1 , having a Formula II

[(Polymerizing Group 1) s -(Amino Acid 1) u -(Internal Spacer) v -(Amino Acid 2) w -(Polymerizing Group 2) y ]  Formula II

where:

polymerizing group 1 and polymerizing group 2 are independently provided by an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate;

each of s and y independently are from 1 to 10;

each amino acid independently is any naturally occurring amino acid, any non-naturally occurring amino acid, for any combination thereof;

u and w sum to at least 2, and are independently 0 to 100;

each internal spacer independently is selected from an amino acid, a peptide, an aliphatic spacer, a heteroaliphatic spacer, a cyclic spacer, a heterocyclic spacer, an aryl spacer, a heteroaryl spacer, or any combination thereof, wherein each internal spacer independently for each occurrence comprises 1 to 20 atoms; and

v is 0 to 20.

9 . The crosslinker according to claim 8 , comprising at least one internal spacer selected from an amino acid, peptide, methylene (—CH 2 —), ethyl (—CH 2 CH 2 —), propyl (—CH 2 CH 2 CH 2 —), butyl (—CH 2 CH 2 CH 2 CH 2 —), pentyl (—CH 2 CH 2 CH 2 CH 2 CH 2 —), hexyl (—CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —),

10 . The crosslinker according to claim 1 , having a Formula III

[(Polymerizing Group 1) s -[(External Spacer 1) t -(Amino Acid) u -(External Spacer 2) x ]-(Polymerizing Group 2) y ]  Formula III,

where:

polymerizing group 1 and polymerizing group 2 independently are provided by reaction with an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate;

each of s and y independently are from 1 to 10;

each amino acid independently is any naturally occurring amino acid, any non-naturally occurring amino acid, or any combination thereof;

u is 2 to 100;

external spacer 1 and external spacer 2 independently are selected from an amino acid, a peptide, an aliphatic spacer, a heteroaliphatic spacer, a cyclic spacer, a heterocyclic spacer, an aryl spacer, a heteroaryl spacer, or any combination thereof, wherein each external spacer 1 and external spacer 2 independently for each occurrence comprises 1 to 20 atoms; and

t and x are 0 to 20.

11 . The crosslinker according to claim 1 having a Formula IV,

[(Polymerizing Group 1) s -(Spacer 1) t -(Amino Acid 1) u -(Spacer 2) v -(Amino Acid 2) w -(Spacer 3) x -(Polymerizing Group 2) y ]  Formula IV,

where:

polymerizing group 1 and polymerizing group 2 independently are provided by reaction with an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate;

each of s and y independently are from 1 to 10;

each amino acid independently is any naturally occurring amino acid, any non-naturally occurring amino acid, or any combination thereof;

u and w sum to at least 2, and independently are 0 to 100;

spacer 1, spacer 2 and spacer 3 independently are selected from an amino acid, a peptide, an aliphatic spacer, a heteroaliphatic spacer, a cyclic spacer, a heterocyclic spacer, an aryl spacer, a heteroaryl spacer, and any and all combinations thereof, wherein each spacer 1, spacer 2, and spacer 3 independently comprises 1 to 20 atoms; and

t, v and x independently are 0 to 20.

12 . The crosslinker according to claim 1 having a Formula V

where:

polymerizing group 1 and polymerizing group 2 independently are provided by reaction with an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate;

each of s and y independently are from 1 to 10;

each amino acid independently is any naturally occurring amino acid, any non-naturally occurring amino acid, or any combination thereof;

u and w sum to at least 2, and are independently 0 to 100;

spacer 1, spacer 2 and spacer 3 independently are selected from an amino acid, a peptide, an aliphatic spacer, a heteroaliphatic spacer, a cyclic spacer, a heterocyclic spacer, an aryl spacer, a heteroaryl spacer, or any combination thereof, wherein each spacer 1, spacer 2, and spacer 3 independently for each occurrence comprises 1 to 20 atoms;

t, v and x are independently 0 to 20;

R 1 is a C 1 -C 10 amine, C 1 -C 10 carboxylic acid, C 1 -C 10 alkene, C 1 -C 10 alkyne, C 1 -C 10 nitrile, C 1 -C 10 alcohol, C 1 -C 10 thiol, C 1 -C 10 phenol, C 4 -C 10 aryl, or C 5 -C 10 heteroaryl; and

z is 0 to 10.

13 . The crosslinker according to claim 12 , where R 1 is C 1 -C 10 NR 2 R 3 or C 1 -C 10 CO 2 R 4 , and where R 2 , R 3 , and R 4 independently are selected from hydrogen or lower alkyl.

14 . The crosslinker according to claim 12 , where R 1 is a C 1 -C 6 -alkyl amine, C 1 -C 6 -alkyl ammonium, C 1 -C 6 —COOH, or C 1 -C 6 —COO − .

15 . The crosslinker according to claim 1 having a Formula VI

where:

polymerizing group 1 and polymerizing group 2 independently are provided by reaction with an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate;

each of s and y independently are from 1 to 10;

each amino acid independently is any naturally occurring amino acid, any non-naturally occurring amino acid, or any combination thereof;

u and w sum to at least 2, and independently are 0 to 100;

spacer 1, spacer 2 and spacer 3 are independently selected from an amino acid, a peptide, an aliphatic spacer, a heteroaliphatic spacer, a cyclic spacer, a heterocyclic spacer, an aryl spacer, or a heteroaryl spacer, wherein each spacer 1, spacer 2, and spacer 3 independently for each occurrence comprises 1 to 20 atoms;

t, v and x independently are 0 to 20;

each R 1 independently is a C 1 -C 10 amine, C 1 -C 10 carboxylic acid, C 1 -C 10 alkene, C 2 -C 10 alkyne, C 1 -C 10 nitrile, C 1 -C 10 alcohol, C 1 -C 10 thiol, C 6 -C 10 phenol, C 6 -C 10 aryl, or C 5 -C 10 heteroaryl; and

z, n, o, p and q independently are 0 to 10.

16 . The crosslinker according to claim 1 , selected from

17 . A hydrogel, having a Formula VII

(Monomer 1) k -(Crosslinker 1) l -(Monomer 2) m   Formula VII

where:

each monomer 1 and monomer 2 independently is provided by reaction with an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate;

k and m independently are 0 to 1000;

crosslinker 1 is the crosslinker according to claim 1 ; and

l is 1 to 100.

18 . The hydrogel according to claim 17 , wherein monomer 1 and monomer 2 comprise a charged monomer.

19 . The hydrogel according to claim 17 , wherein monomer 1 and monomer 2 independently are selected from 2-carboxyethyl acrylate, [2-(acryloyloxy) ethyl] trimethyl ammonium chloride, 3-sulfopropyl methacrylate, [2-(methacryloyloxy) ethyl] trimethyl ammonium chloride, N-(methacryloxyethyl)-N,N-dimethyl-N-(2-methylcarboxyl)ammonium betaine, N-(methacryloxyethyl)-N,N-dimethyl-N-3-sulfopropyl)ammonium betaine, or 2-methacryloyloxyethyl phosphorylcholine.

20 . The hydrogel according to claim 17 , selected from:

21 . A method, comprising:

providing a crosslinker according to claim 1 ; and

forming a hydrogel comprising the crosslinker.

22 . The method according to claim 21 , further comprising using the hydrogel to form a product selected from contact lenses, drug delivery vehicles, tissue engineering platforms, tissue regeneration platforms, catheters, implants, or sensors, wherein the product comprises the hydrogel.

23 . A method for making a crosslinker according to claim 1 , the method comprising:

providing a first protected amino acid comprising a Boc-protected amine, a t-butylester-protected carboxylic acid functional group, and a reactive functional group capable of reacting with a first polymerizing group;

reacting the first protected amino acid with a first polymerizing group selected from an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate to provide a first coupled protected amino acid coupled through the reactive functional group to the first polymerizing group;

selectively removing the Boc protecting group from the first protected amino acid coupled using trifluoracetic acid to provide a first coupled amino acid;

providing a second protected amino acid comprising a Boc-protected amine, an unprotected carboxylic acid, and a reactive functional group capable of reacting with a second polymerizing group;

reacting the second protected amino acid with a second polymerizing group selected from an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate to provide a second coupled protected amino acid coupled through the reactive functional group to the second polymerizing group;

forming a peptide bond between (i) the first coupled amino acid and (ii) the second coupled protected amino acid; and

removing remaining protecting groups to form a crosslinker that is zwitterionic between a pH of 2 to 10.

24 . The method according to claim 23 , further comprising forming a crosslinker comprising at least one spacer group.

25 . A method for making a crosslinker according to claim 1 , the method comprising:

providing a first protected amino acid comprising a Boc-protected amine, an unprotected carboxylic acid functional group, and a reactive functional group capable of reacting with a first polymerizing group;

reacting the first protected amino acid with a first polymerizing group selected from an acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile, or a (hydroxyalkyl) acrylate to provide a first coupled protected amino acid coupled through the reactive functional group to the first polymerizing group;

protecting the unprotected carboxylic acid functional group as a t-butyl ester;

selectively removing the protecting group from the first coupled protected amino acid using trifluoracetic acid to provide an unprotected amine functional group;

providing a second protected amino acid comprising a Boc-protected amine, an unprotected carboxylic acid, and a reactive functional group capable of reacting with a second polymerizing group;

reacting the second protected amino acid with a second polymerizing group selected from acrylate, alkyl acrylate, acrylamide, alkyl acrylamide, acrylonitrile, alkyl acrylonitrile or a (hydroxyalkyl) acrylate to provide a second amine protected amino acid coupled through the reactive functional group to the second polymerizing group;

forming a peptide bond between the first protected amino acid and the second protected amino acid; and

removing remaining protecting groups to form a crosslinker that is zwitterionic between a pH of from 2 to 10.

26 . The method according to claim 25 , further comprising forming a crosslinker comprising at least one spacer group.

27 . A method for forming a crosslinked hydrogel, the method comprising:

providing a crosslinker according to claim 1 ; and

reacting the crosslinker with a first monomer and a second monomer to form the crosslinked hydrogel.