Multi-arm polymer prodrugs
Provided herein are water-soluble prodrugs, compositions comprising such prodrugs, and related methods of making and administering the same. The prodrugs of the invention comprise a water-soluble polymer having three or more arms, at least three of which are typically covalently attached to an active agent, e.g., a small molecule. The conjugates of the invention provide an optimal balance of polymer size and structure for achieving improved drug loading, since the conjugates of the invention possess three or more active agents releasably attached to a multi-armed water-soluble polymer. The prodrugs of the invention are therapeutically effective, and exhibit improved properties in-vivo when compared to unmodified parent drug.
1. A multi-arm polymer prodrug having the structure:
R(-Q-POLY 1 -X-D) q I
wherein
R is an organic radical possessing from 3 to 25 carbon atoms,
Q is a linker, wherein R, when taken together with Q to form R(-Q-) q , is a residue of a polyol after removal of a proton,
POLY 1 is a water-soluble poly(alkylene glycol) polymer,
X is a spacer having an atom length of from 5 atoms to 25 atoms possessing the structure Y—Z, where Y has the structure —(CH 2 ) a —C(O)NH—(CH 2 ) b —(CH 2 CH 2 O) c — and, Z is C(O)—O—, or O—C(O)—O—,
a ranges from 0 to 12,
b ranges from 0 to 12,
c ranges from 0 to 25,
D is a water-soluble camptothecin, and
q is selected from 3, 4, 5, 6, 7, 8, 9, and 10,
or a pharmaceutically acceptable salt form thereof.
2. The multi-arm polymer prodrug of claim 1 , wherein R possesses a number of carbon atoms selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10.
3. The multi-arm polymer prodrug of claim 1 , wherein R is linear.
4. The multi-armed polymer prodrug of claim 1 , wherein R, taken together with Q, is a residue of glycerol, trimethylolpropane, pentaerythritol, sorbitol, or glycerol oligomers.
5. The multi-armed polymer prodrug of claim 4 , wherein Q comprises a heteroatom in addition to said polyol oxygen.
6. The multi-armed polymer prodrug of claim 1 , wherein Q is O.
7. The multi-armed polymer prodrug of claim 1 , wherein POLY 1 is a polyethylene glycol.
8. The multi-armed polymer prodrug of claim 7 , wherein POLY 1 is linear.
9. The multi-armed polymer prodrug of claim 8 , wherein the nominal average molecular weight of POLY 1 ranges from about 200 to about 30,000 daltons.
10. The multi-armed polymer prodrug of claim 9 , wherein the nominal average molecular weight of POLY 1 ranges from about 500 to about 20,000 daltons.
11. The multi-armed polymer prodrug of claim 1 , wherein the nominal average molecular weight of the prodrug is greater than 20,000 daltons.
12. The multi-armed polymer prodrug of claim 1 , wherein X has an atom length of from 5 atoms to 20 atoms.
13. The multi-armed polymer prodrug of claim 1 , wherein
a is selected from 1, 2, 3, and 4,
b is selected from 1, 2, 3, and 4, and
c ranges from 0 to 10.
14. The multi-armed polymer prodrug of claim 1 , wherein Y has the structure: —(CH 2 ) a —C(O)NH—(CH 2 ) 0,1 —(CH 2 CH 2 O) 0-10 —.
15. The multi-armed polymer prodrug of claim 1 , wherein X is either —CH 2 —C(O)—NH—CH 2 —C(O)O— or —CH 2 —C(O)—NH—(CH 2 CH 2 O) 2 —C(O)—O—.
16. The multi-armed polymer prodrug of claim 1 , wherein each of said “q” polymer arms (-Q-POLY 1 -X-D) is the same.
17. The multi-armed polymer prodrug of claim 1 , wherein D is a camptothecin having a molecular weight of less than 800 daltons.
18. The multi-armed polymer prodrug of claim 17 , wherein D has the structure:
and L indicates a site of attachment to X.
19. The multi-armed polymer prodrug of claim 18 , having the structure:
where n ranges from 40 to 500, in the form of a pharmaceutically acceptable salt.
20. The multi-armed polymer prodrug of claim 19 , wherein the overall nominal average molecular weight of the prodrug ranges from about 20,000 to about 80,000 daltons.
21. A pharmaceutical composition comprising a multi-arm polymer prodrug of claim 1 .