Hydrogels with biodegradable crosslinking

1. A hydrogel that is biodegradable under physiological conditions which hydrogel comprises one or more multi-armed PEG polymers crosslinked by a linker that decomposes by a beta elimination reaction,

wherein said linker is

of Formula (1):

wherein for each linker of formula (1):

m of formula (1) is 0 or 1;

X of formula (1) is

wherein

T* is O, S, or NR 6 ;

z is 1-6;

Y is (OCH 2 CH 2 ) p , wherein p is 1-100; and

Z 2 is a first functional group that is coupled to a first cognate group of a first multi-armed polyethylene glycol (PEG) polymer; and

one of R 1 , R 2 , or R 5 comprises a second functional group that is coupled to a second cognate group of a second multi-armed PEG polymer,

wherein each said first functional group and said second functional group independently comprises N 3 , NH 2 , NH—CO 2 t Bu, SH, S t Bu, maleimide, CO 2 H, CO 2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate, or acrylamide;

with the proviso that:

(1) when one of R 5 of formula (1) comprises a second functional group that is coupled to a second cognate group of a second multi-armed PEG polymer, the remaining R 5 of formula (1) is H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH 2 CH 2 ) p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl: and

(a) R 1 and R 2 of formula (1) are independently CN, NO 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR 3 , SOR 3 , SO 2 R 3 , or SR 4 ;

(b) R 1 and R 2 of formula (1) may be joined to form a 3-8 membered ring;

(c) R 1 of formula (1) is CN, NO 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR 3 , SOR 3 , SO 2 R 3 , or SR 4 ; and R 2 of formula (1) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or

(d) R 2 of formula (1) is CN, NO 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR 3 , SOR 3 , SO 2 R 3 , or SR 4 ; and R 1 of formula (1) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or

(2) when R 1 of formula (1) comprises a second functional group that is coupled to a second cognate group of a second multi-armed PEG polymer: R 2 of formula (1) is CN, NO 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR 3 , SOR 3 , SO 2 R 3 , or SR 4 ; and each R 5 of formula (1) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH 2 CH 2 ) p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or

(3) when R 2 of formula (1) comprises a second functional group that is coupled to a second cognate group of a second multi-armed PEG polymer: R 1 of formula (1) is CN, NO 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR 3 , SOR 3 , SO 2 R 3 , or SR 4 ; and each R 5 of formula (1) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH 2 CH 2 ) p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

wherein

R 3 is selected from the group consisting of: (i) H; (ii) optionally substituted alkyl; (iii) optionally substituted aryl; (iv) optionally substituted arylalkyl; (v) optionally substituted heteroaryl; (vi) optionally substituted heteroarylalkyl; (vii) OR 9 ; and (viii) NR 9 2 ;

R 4 is selected from the group consisting of: (i) optionally substituted alkyl; (ii) optionally substituted aryl; (iii) optionally substituted arylalkyl; (iv) optionally substituted heteroaryl; and (v) optionally substituted heteroarylalkyl; and

each R 9 is independently H or optionally substituted alkyl, or both R 9 groups taken together with the nitrogen to which they are attached form a heterocyclic ring.

2. The biodegradable hydrogel of claim 1 , wherein each said first functional group comprises N 3 .

3. The biodegradable hydrogel of claim 1 , wherein in Formula (1)

R 2 is H; and/or

one of R 5 is H and the other is (CH 2 ) n Z, wherein n is 1-6 and Z includes said second functional group.

4. The biodegradable hydrogel of claim 1 , wherein in Formula (1) R 1 is CN or SO 2 R 3 .

5. The biodegradable hydrogel of claim 1 , wherein the first multi-armed PEG polymer and/or second multi-armed PEG polymer comprises the formula [—(CH 2 ) s (CH 2 CH 2 O) n ] t Q, wherein

n is 10-1000;

s is 0-2;

t is 2,4, 8, 16 or 32 and independently represents the number of arms of said multi-armed PEG polymer; and

Q is a core group having a valency t.

6. The biodegradable hydrogel of claim 5 , wherein Q is pentaerythritol, tripentaerythritol, or hexaglycerin.

7. The biodegradable hydrogel of claim 1 , wherein the coupling of the first functional group and the first cognate group comprises a product of:

a reaction of N 3 with acetylene, cyclooctyne, or maleimide;

a reaction of SH with maleimide, acrylate, acrylamide, vinylsulfone, vinylsulfonamide, or halocarbonyl;

a reaction of NH 2 with carboxylic acid or activated carboxylic acid; or

a reaction of maleimide with 1,3-diene, cyclopentadiene, or furan.

8. The biodegradable hydrogel of claim 1 , wherein the coupling of the first functional group and the first cognate group comprises a product of a reaction of N 3 with cyclooctyne.

9. The biodegradable hydrogel of claim 1 , wherein each said second functional group comprises N 3 .

10. The biodegradable hydrogel of claim 1 , wherein the coupling of the second functional group and the second cognate group comprises a product of:

a reaction of N 3 with acetylene, cyclooctyne, or maleimide;

a reaction of SH with maleimide, acrylate, acrylamide, vinylsulfone, vinylsulfonamide, or halocarbonyl;

a reaction of NH 2 with carboxylic acid or activated carboxylic acid; or

a reaction of maleimide with 1,3-diene, cyclopentadiene, or furan.

11. The biodegradable hydrogel of claim 1 , wherein the coupling of the second functional group and the second cognate group comprises a product of a reaction of N 3 with cyclooctyne.