Dendrimer drug conjugates for sustained intra-articular delivery

1. A conjugated dendrimer, represented by the following structural formula:

or a pharmaceutically acceptable salt thereof

wherein:

D is a cationic dendrimer having end groups EG, wherein each EG includes an amine moiety,

each L is a linker;

each API is an active pharmaceutical ingredient;

N is an integer power of 2 from 64 to 256;

x, y, and z, each independently, is an integer from 1 to N; and

wherein:

(i) each CSG is a charge-shielding group having molecular weight of equal to or greater than 200 and less than 400 Da; and

the ratio of (x+y+z)/N is from about 0.6 to about 0.9 or from about 0.4 to about 0.8;

(ii) each CSG is a charge-shielding group having molecular weight of equal to or greater than 400 and less than 614 Da; and

the ratio of (x+y+z)/N is from about 0.2 to about 0.6;

(iii) each CSG is a charge-shielding group having molecular weight of equal to or greater than 614 and less than 820 Da; and

the ratio of (x+y+z)/N is from about 0.15 to about 0.50; or

(iv) each CSG is a charge-shielding group having molecular weight of equal to or greater than 820 and less than or equal to 1085 Da; and

the ratio of (x+y+z)/N is from about 0.1 to about 0.4.

2. The conjugated dendrimer of claim 1 , wherein:

each CSG is a charge-shielding group having molecular weight of equal to or greater than 200 and less than 400 Da;

N is 64; and

the ratio of (x+y+z)/N is from about 0.6 to about 0.9.

3. The conjugated dendrimer of claim 1 , wherein:

each charge-shielding group CSG is a PEG having from 8 to 12 units;

N is 64; and

the ratio of (x+y+z)/N is from about 0.2 to about 0.6.

4. The conjugated dendrimer of claim 1 , wherein:

each charge-shielding group CSG is a PEG having from 8 to 12 units;

the dendrimer D is a polyamidoamine (PAMAM) dendrimer of Generation 4; and

the ratio of (x+y+z/N) is from about 0.3 to about 0.45.

5. The conjugated dendrimer of claim 1 , wherein:

each CSG is a charge-shielding group having molecular weight of equal to or greater than 400 and less than 614 Da;

N is 64; and

the ratio of (x+y+z)/N is from about 0.2 to about 0.6.

6. The conjugated dendrimer of claim 1 , wherein:

each CSG is a charge-shielding group having molecular weight of equal to or greater than 614 and less than 820 Da;

N is 64; and

the ratio of (x+y+z)/N is from about 0.15 to about 0.50.

7. The conjugated dendrimer of claim 1 , wherein:

each CSG is a charge-shielding group having molecular weight of equal to or greater than 820 and less than or equal to 1085 Da;

N is 64; and

the ratio of (x+y+z)/N is from about 0.1 to about 0.4.

8. The conjugated dendrimer of claim 1 , wherein:

each CSG is a charge-shielding group having molecular weight of equal to or greater than 200 and less than 400 Da;

N is 256; and

the ratio of (x+y+z)/N is from about 0.4 to about 0.8.

9. The conjugated dendrimer of claim 1 , wherein:

each charge-shielding group CSG is a PEG having from 8 to 12 units;

N is 256; and

the ratio of (x+y+z)/N is from about 0.2 to about 0.6.

10. The conjugated dendrimer of claim 1 , wherein:

each charge-shielding group CSG is a PEG having from 8 to 12 units;

the dendrimer D is a polyamidoamine (PAMAM) dendrimer of Generation 6; and

the ratio of (x+y+z/N) is from about 0.4 to about 0.5.

11. The conjugated dendrimer of claim 1 , wherein:

each CSG is a charge-shielding group having molecular weight of equal to or greater than 400 and less than 614 Da;

N is 256; and

the ratio of (x+y+z)/N is from about 0.2 to about 0.6.

12. The conjugated dendrimer of claim 1 , wherein:

each CSG is a charge-shielding group having molecular weight of equal to or greater than 614 and less than 820 Da;

N is 256; and

the ratio of (x+y+z)/N is from about 0.15 to about 0.5.

13. The conjugated dendrimer of claim 1 , wherein:

each CSG is a charge-shielding group having molecular weight of equal to or greater than 825 and less than or equal to 1085 Da;

N is 256; and

the ratio of (x+y+z)/N is from about 0.15 to about 0.4.

14. The conjugated dendrimer of claim 1 , wherein the cationic dendrimer includes at least one repeat units represented by the following structural formulas:

15. The conjugated dendrimer of claim 1 , wherein the charge-shielding group is selected from a polyethylene glycol (PEG), a poly(2-oxazoline), a polybetaine, a polyacrylate, a polyacrylamide, an amino acid; a peptide; a fatty acid or phospholipid, an oligosaccharide; a glycosaminoglycan; a polyanhydride, a polyglycidol; a polyacetal; a poly-glycerol, and a polyphosphoester.

16. The conjugated dendrimer of claim 1 , wherein the charge-shielding group is a polyethylene glycol (PEG).

17. The conjugated dendrimer of claim 1 , wherein the linker is represented by any one of the following structural formulas:

18. The conjugated dendrimer of claim 1 , wherein the linker includes a moiety represented by any one of the following structural formulas:

19. The conjugated dendrimer of claim 1 , wherein the linker include a peptide substrate of any one or more of the following enzymes: matrix metalloprotease 13 (MMP13); Cathepsin B; Cathepsin K; ADAMTS-4; and ADAMTS-5.

20. The conjugated dendrimer of claim 1 , wherein the API is selected from a biologically active polypeptide, a monoclonal antibody, a nonsteroidal anti-inflammatory drug (NSAIDS), a matrix metallopeptidase inhibitor, a cytokine inhibitor, and a nucleic acid.

21. The conjugated dendrimer of claim 1 , wherein the API is selected from Insulin-like Growth Factor 1 (IGF-1), a Fibroblast Growth Factor 18 (FGF-18), dexamethasone, a matrix metallopeptidase MMP13 inhibitor, an IL1 receptor antagonist, a TGFB inhibitor, a TNFalpha inhibitor, and kartogenin.

22. The conjugated dendrimer of claim 1 , wherein the cationic dendrimer D is a PAMAM, and each end-group EG is —NH 2 .

23. The conjugated dendrimer of claim 1 , wherein each linker L includes a thiol-maleimide moiety represented by the following structural formula:

24. The conjugated dendrimer of claim 1 , wherein the API is a biologically active polypeptide.

25. The conjugated dendrimer of claim 1 , wherein the cationic dendrimer is a G4 PAMAM, wherein each end-group is —NH 2 and N is 64 or a G6 PAMAM, wherein each end-group is —NH 2 and N is 256.

26. The conjugated dendrimer of claim 25 , wherein each linker L is a thiol-maleimide moiety represented by the following structural formula:

27. The conjugated dendrimer of claim 26 , wherein each API is a human IGF-1.

28. The conjugated dendrimer of claim 1 , wherein the conjugated dendrimer is represented by the following structural formula:

29. A pharmaceutical composition, comprising a conjugated dendrimer of claim 1 in a pharmaceutically acceptable carrier.

30. A method of treating a disorder of an articular joint cartilage, comprising:

administering by an intra-articulate injection to a subject in need thereof a therapeutically effective amount of a conjugated dendrimer of claim 1 ,

wherein the disorder is an articular joint arthritis or an articular joint cartilage injury.