Factor VIII zwitterionic polymer conjugates
The present invention provides multi-armed high MW polymers containing hydrophilic groups conjugated to Factor VIII, and methods of preparing such polymers.
1. A compound having the following formula:
R1-R2 R3) s ;
wherein s is 1-20;
R1 is selected from the group consisting of —NH 2 , —OH, and —SH;
R2 is selected from the group consisting of unsubstituted alkyl, unsubstituted alkylene, unsubstituted alkoxy, carboxyalkyl, haloalkyl, cycloalkyl, cyclic alkyl ether, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkylene, heterocycloalkyl, heterocycloalkylene, aryl, arylene, arylene-oxy, heteroaryl, amino, amido and a combination thereof; and
R3 is
wherein R4, R5, and R6 are the same or different and are selected from the group consisting of:
and
wherein Z is —NCS, —F, —Cl, —Br, —I, or polymer, the polymer is synthesized with a monomer selected from the group consisting of:
wherein
R7 is H or C 1-6 alkyl, ZW is a zwitterion, and t is 1 to 6.
2. The compound of claim 1 , wherein R2 comprises a structure having the formula:
wherein m is an integer from 1 to 20.
3. The compound of claim 2 , wherein R2 is:
wherein X is an integer from 0 to 50, and Y is an integer from 1 to 50.
4. The compound of claim 1 , wherein the zwitterion is phosphorylcholine.
5. The compound of claim 1 , wherein Z is the polymer, and the monomer is 2-(methacryloyloxyethyl)-2′-(trimethylammoniumethyl) phosphate (MPC) or 2-(acryloyloxyethyl)-2′-(trimethylammoniumethyl) phosphate.
6. The compound of claim 5 , wherein the monomer is 2-(methacryloyloxyethyl)-2′-(trimethylammoniumethyl) phosphate (MPC).
7. The compound according to claim 6 , wherein R2 is:
Y is an integer from 1 to 10; and X is 4, 8, or 12.
8. The compound according to claim 7 , wherein Y is 4.
9. The compound of claim 1 , wherein Z is —Br.
10. The compound according to claim 1 , wherein the total molecular weight of the compound is about 500,000 to about 1,000,000 daltons.
11. The compound according to claim 10 , wherein the total molecular weight of the compound is about 650,000 to about 850,000 daltons.
12. The compound according to claim 11 , wherein the total molecular weight of the compound is about 750,000 daltons.
13. The compound of claim 1 , wherein Z is —NCS, —F, —Cl, —Br, or —I.
14. The compound of claim 13 having the following formula:
and
wherein Y is an integer from 1 to 50, and X is an integer from 0 to 50.
15. The compound of claim 1 having the following formula:
and
wherein Y is an integer from 1 to 50, X is an integer from 0 to 50, and MPC is polyMPC arm.
16. A method of synthesizing a linker-polymerized initiator comprising:
combining the compound of claim 13 with monomers selected from the group consisting of:
wherein R7 is H or C 1-6 alkyl, ZW is a zwitterion, and t is 1 to 6, thereby forming a polymerized initiator; and
coupling a linker moiety comprising second and third reactive groups to the polymerized initiator to provide a linker-polymerized initiator having an unreacted reactive group.
17. The method of claim 16 , wherein the linker moiety is
wherein:
R8 is
and
R9 is selected from the group consisting of:
wherein P is an integer from 1 to 12.
18. The method of claim 16 , wherein the compound is further represented by the following formula:
and
wherein Y is an integer from 1 to 50, X is an integer from 0 to 50 and Z is —NCS, —F, —Cl, —Br, or —I.
19. The method of claim 16 , wherein the polymerized initiator has the following formula:
and
wherein Y is an integer from 1 to 50, X is an integer from 0 to 50, and MPC is polyMPC arm.
20. The method of claim 16 , wherein the linker-polymerized initiator has the following formula:
and
wherein Y is an integer from 1 to 50, X is an integer from 0 to 50, and polymer is synthesized with a monomer selected from the group consisting of:
wherein R7 is H or C 1-6 alkyl, ZW is a zwitterion, and t is 1 to 6.