Multi-armed, monofunctional, and hydrolytically stable derivatives of poly (ethylene glycol) and related polymers for modification of surfaces and molecules
View Patent ↗Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms poly a and poly b , respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure where mPEG a and mPEG b have the structure CH 3 O—(CH 2 CH 2 O) n CH 2 CH 2 — wherein n may be the same or different for poly a - and poly b - and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000.
1. A monofunctional water-soluble polymer having the structure:
where:
R is H,
C is carbon,
Z is a moiety comprising a single reactive site, X, at its terminus,
poly a and poly b are each independently CH 3 O(CH 2 CH 2 O) n CH 2 CH 2 —, where n in each of poly a and poly b ranges from 1 to 1150, and
P and Q are each independently a hydrolytically stable linker fragment comprising from 1 to 10 atoms, each linker fragment (i) joined to poly a or poly b , respectively, by an ether linkage, and (ii) absent an aromatic ring.
2. The monofunctional water soluble polymer of claim 1 , having the structure:
wherein Z is —R z —X, where R z is a linear linkage fragment attached to the central carbon, C, and X is the terminal reactive site.
3. The monofunctional water soluble polymer of claim 2 , wherein R z comprises an amide linkage.
4. The monofunctional water soluble polymer of claim 3 , wherein R z comprises an amide linkage covalently attached to an alkylene chain.
5. The monofunctional water soluble polymer of claim 1 , wherein —P—CH(Q-)Z is formed from an alcohol having more than two hydroxyl groups.
6. The monofunctional water soluble polymer of claim 2 , wherein —P—CH(Q-)Z is formed from an alcohol having more than two hydroxyl groups.
7. The monofunctional water soluble polymer of claim 4 , wherein —P—CH(Q-)Z is formed from an alcohol having more than two hydroxyl groups.
8. The monofunctional water soluble polymer of claim 1 , wherein P is an alkyl fragment joined to poly a by an ether linkage.
9. The monofunctional water soluble polymer of claim 2 , wherein P is an alkyl fragment joined to poly a by an ether linkage.
10. The monofunctional water soluble polymer of claim 4 , wherein P is an alkyl fragment joined to poly a by an ether linkage.
11. The monofunctional water soluble polymer of claim 2 , wherein the reactive site is selected from carboxyl and activated carboxyl.
12. The monofunctional water soluble polymer of claim 10 , wherein the reactive site is selected from carboxyl and activated carboxyl.
13. The monofunctional water soluble polymer of claim 2 , wherein the reactive site is selected from active esters, active carbonates, and maleimide.
14. The monofunctional water soluble polymer of claim 10 , wherein the reactive site is selected from active esters, active carbonates, and maleimide.
15. The monofunctional water soluble polymer of claim 14 , wherein the reactive site is selected from N-hydroxysuccinimidyl ester and maleimide.
16. The monofunctional water soluble polymer of claim 1 covalently attached via the single reactive site of Z to a biologically active molecule.
17. The monofunctional water soluble polymer of claim 16 , wherein said biologically active molecule is a protein.
18. The monofunctional water soluble polymer of claim 10 covalently attached via the single reactive site of Z to a biologically active molecule.
19. A conjugate formed by reacting the monofunctional water soluble polymer of claim 1 with a biologically active molecule.
20. The monofunctional water soluble polymer of claim 1 wherein P and Q are the same.
21. The monofunctional water soluble polymer of claim 1 wherein P and Q are different.