Stabilized polymeric thiol reagents
View Patent ↗Disclosed are water soluble polymeric conjugates comprising the structure POLY-[Y—S—S-A] x , where POLY is a water soluble polymer; Y is a hydrocarbon-based spacer group, x is 1 to 25, S—S is a disulfide group attached to an sp 3 hybridized carbon of Y; and A is a covalently linked residue of a pharmacologically active molecule. Preferably, the water soluble polymer is a PEG polymer. Also disclosed are polymeric reagents useful to prepare such conjugates, and methods of their formation and use.
1. A polymer conjugate comprising the structure:
POLY—[Y—S—S—A] x
wherein:
POLY is a water soluble polymer;
Y has the formula —(CR 1 R 2 ) n —, where n is 4 to 8, each of R 1 and R 2 is independently selected from hydrogen, lower alkyl, lower alkenyl, and a non-interfering substituent, where two groups R 1 and R 2 on different carbon atoms may be linked to form a cycloalkyl or aryl group;
S—S is a disulfide group attached to an sp 3 hybridized carbon of Y; and
A is a covalently linked residue of a pharmacologically active molecule; and
x is 1-25, and
if POLY is a linear polyethylene glycol, x=1, and Y is a linear alkyl chain, the POLY has a molecular weight of at least 500,
wherein when POLY is a linear polyethylene glycol, at least one R 1 on a carbon adjacent to said disulfide linkage is lower alkyl.
2. The conjugate of claim 1 , wherein said conjugate is water soluble.
3. The conjugate of claim 2 , wherein x is 1.
4. The conjugate of claim 2 , wherein x is 2.
5. The conjugate of claim 1 , wherein POLY is a polyethylene glycol.
6. The conjugate of claim 5 , wherein said polyethylene glycol has a molecular weight of 148 to about 100,000 Daltons and a morphology selected from linear, branched, forked, and multiarmed.
7. The conjugate of claim 2 , wherein each of R 1 and R 2 is independently selected from hydrogen and lower alkyl.
8. The conjugate of claim 7 , wherein each of R 1 and R 2 is independently selected from hydrogen and methyl.
9. The conjugate of claim 8 , wherein each of R 1 and R 2 is hydrogen.
10. The conjugate of claim 9 , wherein each of R 1 and R 2 is hydrogen with the exception of R 1 on a carbon adjacent said sulfur atom, said R 1 being lower alkyl.
11. The conjugate of claim 2 , wherein two groups R 1 and R 2 on different carbon atoms are linked to form a cycloalkyl or aryl group.
12. The conjugate of claim 1 , wherein said molecule has a reactive thiol group in its unconjugated form and is selected from the group consisting of proteins, peptides, and small molecules.
13. The conjugate of claim 1 , comprising the structure: A—S—S—Y—POLY-Y—S—S-A.
14. The conjugate of claim 13 , wherein the Y groups are identical.
15. The conjugate of claim 1 , in combination with a pharmaceutical excipient.
16. The conjugate of claim 15 , wherein said excipient is an aqueous carrier.