System for delivering therapeutic agents into living cells and cells nuclei

1. A phosphate based oligomeric compound, comprising a repeating unit defined by the structure of formula (A):

and a first linker, which links between the phosphate groups of two of said repeating units (“a splitting linker”), said linker is defined by the structure of formula (B):

wherein

Y is a delivery group or a protected delivery group; wherein said delivery group is amine, histidine, guanidine, polyguanidine, imidazole, polyimidzole or any combination thereof;

w , w′ and w″ are each independently an integer between 0 and 10; and

p is an integer between 0 and 10.

2. The oligomeric compound of claim 1 , further comprising at least one end linker, which is attached to the terminus of said oligomeric compound;

wherein

said end linker is independently a substituted or unsubstituted linear alkyl chain of 2-50 carbon atoms, substituted or unsubstituted linear alkylphosphate chain of 2-50 carbon atoms, substituted or unsubstituted branched alkylphosphate chain of 2-50 carbon atoms, substituted or unsubstituted linear alkylether chain of 2-50 carbon atoms or any combination thereof.

3. The oligomeric compound of claim 1 , further comprising additional linkers (“second linker”), which are the same or different, each links between two consecutive repeating units of said oligomeric compound;

wherein

each of said second linkers is independently a substituted or unsubstituted linear alkyl chain of 2-50 carbon atoms, substituted or unsubstituted linear alkylphosphate chain of 2-50 carbon atoms, substituted or unsubstituted branched alkylphosphate chain of 2-50 carbon atoms, substituted or unsubstituted linear alkylether chain of 2-50 carbon atoms or any combination thereof.

4. The phosphate based oligomeric compound according to claim 2 , wherein said end linker is hexyl.

5. The phosphate based oligomeric compound according to claim 3 , wherein each of said second linkers is hexylphosphate.

6. The phosphate based oligomeric compound according to claim 3 , wherein said alkyl ether chain of said second linker and/or end linkers is polyethyleneglycol (PEG).

7. The phosphate based oligomeric compound according to claim 3 , wherein said compound is defined by the structure of formula III(ea):

wherein

each of Z 1 and Z 2 is independently a reactive group capable of binding a biologically active moiety; or a hydrogen atom, provided that at least one of Z 1 and Z 2 is a reactive group wherein said reactive group is hydroxy, amine, halide, a phosphorous-containing group, —NH—CO—NH 2 , —NH—CS—NH 2 C-amide, N-amide, thiol or COOH;

Y is a delivery group or a protected delivery group, wherein said delivery group or protected delivery group is amine, protected amine, histidine, guanidine, trifluoroacetamide, FMOC, FMS, polyguanidine, imidazole, polyimidzole or any combination thereof;

r is an integer number of between 0 and 50; and

q is an integer between 0 and 10.

8. The compound according to claim 7 , wherein said compound is defined by the structure of formula III:

wherein Z 1 and Z 2 are as defined in claim 7 .

9. The compound according to claim 7 , wherein said compound is defined by the structure of formula III(x):

wherein Z 1 and Z 2 are as defined in claim 7 .

10. The phosphate based oligomeric compound according to claim 2 , wherein said compound is defined by the structure of formula III(f):

wherein

each of Z 1 and Z 2 is independently a reactive group capable of binding a biologically active moiety; or a hydrogen atom, provided that at least one of Z 1 and Z 2 is a reactive group wherein said reactive group is hydroxy, amine, halide, a phosphorous-containing group, —NH—CO—NH 2 , —NH—CS—NH 2 C-amide, N-amide, thiol or COOH;

E is an end linker or absent; wherein said third linking group is a linear alkyl of 2-50 carbon atoms;

Y is a delivery group or a protected delivery group, wherein said delivery group or protected delivery group is amine, protected amine, histidine, guanidine, trifluoroacetamide, FMOC, FMS, polyguanidine, imidazole, polyimidzole or any combination thereof; and

each of r and r′ is independently an integer number of between 1 and 50.

11. The compound according to claim 10 wherein said compound is defined by the structure of formula III(a):

wherein Z 1 and Z 2 are as defined in claim 10 .

12. The compound according to claim 10 wherein said compound is defined by the structure of formula III(xx):

wherein Z 1 and Z 2 are as defined in claim 10 .

13. A conjugate of the phosphate based oligomeric compound of claim 1 and at least one biologically active substance, wherein said biologically active substance is covalently attached to the terminus of said oligomeric compound.

14. A conjugate of the phosphate based oligomeric compound of claim 3 and at least one biologically active substance, wherein said biologically active substance is covalently attached to the terminus of said oligomeric compound.

15. The conjugate of claim 14 , defined by the structure of formula IV(da):

wherein

each of T 1 and T 2 is independently a biologically active moiety or absent, wherein at least one of T 1 and T 2 is present; and wherein said biologically active substance is a therapeutically active agent, a labeling moiety, or combination thereof;

each of Z 1 ′, Z 2 ′, is independently a derivative of Z 1 and Z 2 , respectively, as a result of binding the biologically active group, wherein said Z 1 and Z 2 reactive group is hydroxyl, amine, halide, a phosphorous-containing group, a phosphate, C-amide, N-amide, thiol or COOH; and

Y is a delivery group or a protected delivery group, wherein said delivery group or protected delivery group is amine, protected amine, histidine, guanidine, trifluoroacetamide, FMOC, FMS, polyguanidine, imidazole, polyimidzole or any combination thereof;

r and r′ are each independently an integer number of between 0 and 50; and

q is an integer between 0 and 10;

wherein if T 1 or T 2 is absent then Z 1 ′ or Z 2 ′ connected to it is replaced with Z 1 or Z 2 respectively.

16. The conjugate according to claim 15 , defined by the structure of formula IV(h):

wherein

T 1 , T 2 , Z 1 ′ and Z 2 ′ are as defined in claim 15 .

17. The conjugate according to claim 16 , wherein said conjugate is defined by the structure of formula V:

18. The conjugate of claim 13 , defined by the structure of formula IV(m):

wherein

each of T 1 and T 2 is independently a biologically active moiety or absent, wherein at least one of T 1 and T 2 is present; and wherein said biologically active substance is a therapeutically active agent, a labeling moiety, or combination thereof;

each of Z 1 ′, Z 2 ′, is independently a derivative of Z 1 and Z 2 , respectively, as a result of binding the biologically active group,

wherein said Z 1 and Z 2 is independently a reactive group capable of binding a biologically active moiety; or a hydrogen atom, provided that at least one of Z 1 and Z 2 is a reactive group wherein said reactive group is hydroxy, amine, halide, a phosphorous-containing group, —NH—CO—NH 2 , —NH—CS—NH 2 C-amide, N-amide, thiol or COOH;

E is an end linker or absent; wherein said third linking group is a linear alkyl of 2-50 carbon atoms;

Y is a delivery group or a protected delivery group, wherein said delivery group or protected delivery group is amine, protected amine, histidine, guanidine, trifluoroacetamide, FMOC, FMS, polyguanidine, imidazole, polyimidzole or any combination thereof; and

each of r and r′ is independently an integer number of between 1 and 50;

wherein if T 1 or T 2 is absent then Z 1 ′ or Z 2 ′ , is replaced with Z 1 or Z 2 respectively.

19. The conjugate according to claim 18 , defined by the structure of formula IV(a):

wherein

T 1 , T 2 , Z 1 ′ and Z 2 ′ are as defined in claim 18 .

20. The conjugate according to claim 19 , wherein said conjugate is defined by the structure of formula V(b):

21. The oligomer of claim 7 , wherein r is 3.

22. The oligomer of claim 10 , wherein r and r′ are both 8.

23. The conjugate of claim 15 , wherein r and r′ are both3.

24. The conjugate of claim 18 , wherein r and r′ are both 8.

25. A complex of the conjugate according to claim 13 and an oligonucleotide, wherein said oligonucleotide, is electrostatically bound to said conjugate.

26. The complex according to claim 25 , wherein said oligonucleotide is DNA, RNA or combination thereof.

27. The complex according to claim 26 , wherein said RNA is siRNA.

28. A method of delivering a DNA, RNA or combination thereof to a cell, said method comprises contacting said complex of claim, 26 with said cell, thereby delivering said DNA, RNA or combination thereof to said cell.

29. The method of claim 28 , wherein said cell is cancerous.

30. A method of treating cancer, comprising administering a complex of claim 26 to a subject, thereby treating cancer.

31. The method of claim 30 wherein said cancer is pancreatic cancer, glioblastoma or lung cancer.

32. A method of diagnosing a condition, comprising contacting said conjugate of claim 13 with a cell, wherein said biologically active substance in said conjugate is a labeling moiety, thereby delivering the labeling moiety of said conjugate to said cell and diagnosing said condition.

33. A pharmaceutical composition comprising the conjugate of claim 13 and a pharmaceutically acceptable carrier.

34. A pharmaceutical composition comprising the complex of claim 25 and a pharmaceutically acceptable carrier.