Dual phase drug release system

1. A conjugate comprising a carrier substituted with one or more occurrences of a moiety having the structure:

wherein:

each occurrence of M is independently a modifier having a molecular weight ≦10 kDa;

the modifier M is directly or indirectly attached to a linker L M through an amide bond;

the carrier is a polyacetal or polyketal and is linked directly or indirectly to each occurrence of a linker L M through an ester bond;

denotes direct or indirect attachment of M to linker L M ; and

each occurrence of a linker L M independently comprises a moiety having the structure:

wherein:

denotes the site of attachment to the modifier M; p is an integer from 1-12; q is an integer from 0-4; R 1 is hydrogen, —C(═O)R 1A , —C(═O)OR 1A , —SR 1A , SO 2 R 1A or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, aromatic, heteroaromatic moiety, wherein each occurrence of R 1A is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aromatic, heteroaromatic, aryl or heteroaryl; and each occurrence of R and R 2 is independently hydrogen, halogen, —CN, NO 2 , an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, aromatic, heteroaromatic moiety, or -GR G1 wherein G is —O—, —S—, —NR G2 —, —C(═O)—, —S(═O)—, —SO 2 —, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)—, —OC(═O)O—, —OC(═O)NR G2 —, —NR G2 C(═O)O—, —NR G2 C(═O)NR G2 —, —C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—, —C(═NR G2 )—, —C(═NR G2 )O—, —C(═NR G2 )NR G3 —, —OC(═NR G2 )—NR G2 C(═NR G3 )—, —NR G2 SO 2 —, —NR G2 SO 2 NR G3 —, or —SO 2 NR G2 —, wherein each occurrence of R G1 , R G2 and R G3 is independently hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl or heteroaryl moiety.

2. The conjugate of claim 1 , wherein p is 1.

3. The conjugate of claim 1 , wherein p is 1 and R is hydrogen.

4. The conjugate of claim 1 , wherein each occurrence of M is CPT or Taxol.

5. The conjugate of claim 1 , wherein q is 0, p is 1, R and R 1 are each hydrogen, and each occurrence of M is CPT or Taxol.

6. A conjugate comprising a carrier substituted with one or more occurrences of a moiety having the structure:

wherein each occurrence of M is independently a modifier having a molecular weight <10 kDa;

denotes direct or indirect attachment of M to linker L M ; and

each occurrence of a linker L M independently comprises a moiety having the structure:

wherein

 denotes the site of attachment to the modifier M;

 denotes the site of attachment to the carrier; q is an integer from 0-4; R 1 is hydrogen, —C(═O)R 1A , —C(═O)OR 1A , —SR 1A , SO 2 R 1A or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, aromatic, heteroaromatic moiety, wherein each occurrence of R 1A is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aromatic, heteroaromatic, aryl or heteroaryl; and each occurrence of R 2 is independently hydrogen, halogen, —CN, NO 2 , an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, aromatic, heteroaromatic moiety, or -GR G1 wherein G is —O—, —S—, —NR G2 —, —C(═O)—, —S(═O)—, —SO 2 —, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)—, —OC(═O)O—, —OC(═O)NR G2 —, —NR G2 C(═O)O—, —NR G2 C(═O)NR G2 —, —C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—, —C(═NR G2 )—, —C(═NR G2 )O—, —C(═NR G2 )NR G3 —, —OC(═NR G2 )—, —NR G2 C(═NR G3 )—, —NR G2 SO 2 —, —NR G2 SO 2 NR G3 —, or —SO 2 NR G2 —, wherein each occurrence of R G1 , R G2 and R G3 is independently hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl or heteroaryl moiety;

whereby the modifier M is directly or indirectly attached to a linker L M through an amide bond, the carrier is linked directly or indirectly to each occurrence of a linker L M through an ester bond, and wherein the carrier is a polyacetal, wherein at least one occurrence of M comprises CPT or Taxol, and wherein CPT or Taxol is indirectly attached to linker L M via a glycine moiety.

7. A conjugate comprising a carrier substituted with one or more occurrences of a moiety having the structure:

wherein each occurrence of M is independently a modifier having a molecular weight ≦10 kDa;

denotes direct or indirect attachment of M to linker L M ; and

each occurrence of a linker L M independently comprises a moiety having the structure:

wherein

 denotes the site of attachment to the modifier M;

 denotes the site of attachment to the carrier; q is an integer from 0-4; R 1 is hydrogen, —C(═O)R 1A , —C(═O)OR 1A , —SR 1A , SO 2 R 1A or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, aromatic, heteroaromatic moiety, wherein each occurrence of R 1A is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aromatic, heteroaromatic, aryl or heteroaryl; and each occurrence of R 2 is independently hydrogen, halogen, —CN, NO 2 , an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, aromatic, heteroaromatic moiety, or -GR G1 wherein G is —O—, —S—, —NR G2 —, —C(═O)—, —S(═O)—, —SO 2 —, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)—, —OC(═O)O—, —OC(═O)NR G2 —, —NR G2 C(═O)O—, —NR G2 C(═O)NR G2 —, —C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—, —C(═NR G2 )—, —C(═NR G2 )O—, —C(═NR G2 )NR G3 —, —OC(═NR G2 )—, —NR G2 C(═NR G3 )—, —NR G2 SO 2 —, —NR G2 SO 2 NR G3 —, or —SO 2 NR G2 —, wherein each occurrence of R G1 , R G2 and R G3 is independently hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl or heteroaryl moiety;

whereby the modifier M is directly or indirectly attached to a linker L M through an amide bond, the carrier is linked directly or indirectly to each occurrence of a linker L M through an ester bond, and wherein the carrier is a polyacetal, wherein each occurrence of M comprises CPT or Taxol, and wherein CPT or Taxol is indirectly attached to linker L M via a glycine moiety.

8. The conjugate of claim 6 or 7 , comprising a PHF-CPT conjugate having n occurrences of the bracketed structure n, k occurrences of the bracketed structure k, and m occurrences of the bracketed structure m:

wherein n, k and m are integers between 10-300, 1-20, and 0-300 respectively.

9. The conjugate of claim 6 or 7 , comprising a PHF-Taxol conjugate having n occurrences of the bracketed structure n, k occurrences of the bracketed structure k, and m occurrences of the bracketed structure m:

wherein n, k and m are integers between 10-300, 1-20, and 0-300 respectively.

10. The PHF-CPT conjugate of claim 8 , wherein the

moiety has the structure:

11. The PHF-Taxol conjugate of claim 9 , wherein the

moiety has the structure:

12. The conjugate of claim 1 , wherein each occurrence of M is CPT.

13. The conjugate of claim 1 , wherein each occurrence of M is taxol.

14. The conjugate of claim 5 , wherein each occurrence of M is CPT.

15. The conjugate of claim 5 , wherein each occurrence of M is taxol.

16. The conjugate of claim 7 , wherein each occurrence of M is CPT.

17. The conjugate of claim 7 , wherein each occurrence of M is taxol.

18. The conjugate of claim 6 , wherein at least one occurrence of M comprises CPT.

19. The conjugate of claim 6 , wherein at least one occurrence of M comprises taxol.

20. A composition comprising the conjugate of claim 1 and a pharmaceutically suitable carrier or diluent.

21. A composition comprising the conjugate of claim 6 and a pharmaceutically suitable carrier or diluent.

22. A composition comprising the conjugate of claim 7 and a pharmaceutically suitable carrier or diluent.

23. The conjugate of claim 1 , wherein the carrier is PHF (poly(1-hydroxymethylethylene hydroxymethyl-formal)).

24. The conjugate of claim 5 , wherein the carrier is PHF (poly(1-hydroxymethylethylene hydroxymethyl-formal)).

25. The conjugate of claim 6 , wherein the carrier is PHF (poly(1-hydroxymethylethylene hydroxymethyl-formal)).

26. The conjugate of claim 7 , wherein the carrier is PHF (poly(1-hydroxymethylethylene hydroxymethyl-formal)).

27. The conjugate of claim 14 , wherein the carrier is PHF (poly(1-hydroxymethylethylene hydroxymethyl-formal)).

28. The composition of claim 20 , wherein the carrier is PHF (poly(1-hydroxymethylethylene hydroxymethyl-formal)).

29. The composition of claim 21 , wherein the carrier is PHF (poly(1-hydroxymethylethylene hydroxymethyl-formal)).

30. The composition of claim 22 , wherein the carrier is PHF (poly(1-hydroxymethylethylene hydroxymethyl-formal)).