Branched water-soluble polymers and their conjugates
View Patent ↗The present invention provides branched water-soluble polymers that allow two or more water-soluble polymers to be conjugated to another species. The branched polymers provide access to therapeutic agents that are conjugated at a single site to two or more water-soluble polymers. The branched polymers are based upon branch points that are simple branched alkyl structures, reactive side-chain amino acids and small peptides of reactive side-chain amino acids, and saccharides. Also provided is a method for preparing mono-disperse poly(ethylene glycol) of a well-defined and determinable molecular weight, and a method for the rational end-functionalization of poly(ethylene glycol). Conjugates of the branched water-soluble polymers with diverse species, e.g., peptides, lipids, glycolipids and small molecules are also provided.
1. A branched water-soluble polymer having the formula:
in which
R 16 , R 16′ , R 17 , R 18 and R 19 are members independently selected from H, OH, NH 2 , NHAc and:
wherein
Z 2 is a member selected from O, S, CH 2 and S
R 11 is a water-soluble polymer, and
the index “a” represents an integer from 0 to 20,
with the proviso that at least two of R 16 , R 16 ′, R 17 , R 18 and R 19 have a structure according to Formula I; and
R 15 is a member selected from H, a nucleotide sugar, and a bond to a carrier molecule, wherein the carrier molecule is a member selected from a peptide, glycopeptide, lipid, glycolipid, protein, glycoprotein, saccharide, hormone, receptor, antigen, transition state analog, cofactor, drug, dye, nutrient, growth factor, solid support, virus, and microorganism.
2. The branched water-soluble polymer according to claim 1 , wherein said water-soluble polymer comprises poly(ethylene glycol).
3. The branched water-soluble polymer according to claim 1 , wherein said carrier molecule is a peptide, glycopeptide, lipid, or glycolipid.
4. The branched water-soluble polymer according to claim 1 , wherein R 15 is a nucleotide sugar.
5. The branched water-soluble polymer according to claim 4 , wherein the nucleotide sugar is cytidine monophosphate (CMP).
6. The branched water-soluble polymer according to claim 1 , wherein said carrier molecule is a protein, glycoprotein, saccharide, hormone, receptor, antigen, transition state analog, cofactor, drug, dye, nutrient, growth factor, solid support, virus, or microorganism.
7. The branched water-soluble polymer according to claim 2 , wherein said poly(ethylene glycol) has a molecular weight selected from 5 kD, 10 kD, 20 kD, and 30 kD.
8. The branched water-soluble polymer according to claim 7 , wherein said poly(ethylene glycol) has a molecular weight of 20 kD.
9. The branched water-soluble polymer according to claim 3 , wherein said water-soluble polymer comprises poly(ethylene glycol).
10. The branched water-soluble polymer according to claim 9 , wherein said poly(ethylene glycol) has a molecular weight selected from 5 kD, 10 kD, 20 kD, and 30 kD.
11. The branched water-soluble polymer according to claim 10 , wherein said poly(ethylene glycol) has a molecular weight of 20 kD.
12. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 1 and a pharmaceutically acceptable carrier.
13. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 2 and a pharmaceutically acceptable carrier.
14. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 3 and a pharmaceutically acceptable carrier.
15. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 7 and a pharmaceutically acceptable carrier.
16. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 8 and a pharmaceutically acceptable carrier.
17. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 9 and a pharmaceutically acceptable carrier.
18. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 10 and a pharmaceutically acceptable carrier.
19. A pharmaceutical formulation comprising the branched water-soluble polymer according to claim 11 and a pharmaceutically acceptable carrier.