Taxane silicate prodrugs and nanoparticles
The invention provides silicate prodrugs comprising a therapeutic agent linked to one or more groups of formula (I): —Si(OR) 3 (I); wherein each R independently has any of the values defined herein, as well as nanoparticles comprising such compounds.
1. A compound comprising a taxane linked to one or more groups of formula (I):
—Si(OR) 3 (I)
wherein:
each R is independently selected from (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, (C 2 -C 20 )alkynylcarbonyl, wherein each (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, is optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, oxo, halo, or aryl.
2. The compound of claim 1 wherein the taxane is a paclitaxel or docetaxel.
3. A compound of formula (Ia):
wherein R 1 is a group of formula (I),
—Si(OR) 3 (I)
wherein:
each R is independently selected from (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, wherein each (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, is optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, oxo, halo, or aryl;
or a salt thereof.
4. A compound of formula (Ib):
wherein R 1 and R 2 are each independently a group of formula (I),
—Si(OR) 3 (I)
wherein:
each R is independently selected from (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, wherein each (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, is optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, oxo, halo, or aryl;
or a salt thereof.
5. A compound of formula (Ic):
wherein R 3 is a group of formula (I),
—Si(OR) 3 (I)
wherein:
each R is independently selected from (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, wherein each (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, is optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, oxo, halo, or aryl;
or a salt thereof.
6. A compound selected from:
and salts thereof.
7. A compound selected from:
and salts thereof.
8. A composition comprising a compound as described in claim 1 and a PEG-b-PLGA block co-polymer.
9. A composition comprising a compound as described in claim 1 and a pharmaceutically acceptable carrier.
10. A nano-particle comprising a compound as described in claim 1 and a PEG-b-PLGA block co-polymer.
11. A nano-particle comprising a compound as described in claim 1 and one or more targeting moieties.
12. A method to treat cancer in an animal comprising administering to the animal a compound as described in claim 1 .
13. A method to treat restenosis in an animal comprising administering to the animal a compound as described in claim 1 .
14. A method to treat cancer in an animal, comprising administering to the animal a nano-particle as described in claim 10 .
15. A composition comprising a compound as described in claim 3 and a PEG-b-PLGA block co-polymer.
16. A composition comprising a compound as described in claim 3 and a pharmaceutically acceptable carrier.
17. A nano-particle comprising a compound as described in claim 3 and a PEG-b-PLGA block co-polymer.
18. A nano-particle comprising a compound as described in claim 3 and one or more targeting moieties.
19. A method to treat cancer in an animal comprising administering to the animal a compound as described in claim 3 .
20. A method to treat restenosis in an animal comprising administering to the animal a compound as described in claim 3 .
21. A method to treat cancer in an animal, comprising administering to the animal a nano-particle as described in claim 17 .
22. A composition comprising a compound as described in claim 4 and a PEG-b-PLGA block co-polymer.
23. A composition comprising a compound as described in claim 4 and a pharmaceutically acceptable carrier.
24. A nano-particle comprising a compound as described in claim 4 and a PEG-b-PLGA block co-polymer.
25. A nano-particle comprising a compound as described in claim 4 and one or more targeting moieties.
26. A method to treat cancer in an animal comprising administering to the animal a compound as described in claim 4 .
27. A method to treat restenosis in an animal comprising administering to the animal a compound as described in claim 4 .
28. A method to treat cancer in an animal, comprising administering to the animal a nano-particle as described in claim 4 .
29. A composition comprising a compound as described in claim 5 and a PEG-b-PLGA block co-polymer.
30. A composition comprising a compound as described in claim 5 and a pharmaceutically acceptable carrier.
31. A nano-particle comprising a compound as described in claim 5 and a PEG-b-PLGA block co-polymer.
32. A nano-particle comprising a compound as described in claim 5 and one or more targeting moieties.
33. A method to treat cancer in an animal comprising administering to the animal a compound as described in claim 5 .
34. A method to treat restenosis in an animal comprising administering to the animal a compound as described in claim 5 .
35. A method to treat cancer in an animal, comprising administering to the animal a nano-particle as described in claim 31 .