System for delivering therapeutic agents into living cells and cells nuclei
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-015/113
C07F-009/09
C07F-009/6561
A61K-047/48
C12N-015/11
A61K-049/00
C08G-083/00
G01N-033/50
출원번호
US-0690499
(2015-04-20)
등록번호
US-9822134
(2017-11-21)
발명자
/ 주소
Segev, David
출원인 / 주소
SABAG-RFA LTD.
대리인 / 주소
Cohen, Mark S.
인용정보
피인용 횟수 :
0인용 특허 :
28
초록▼
The present invention relates to a novel delivery system for delivering therapeutic agents into living cells, and more particularly, to novel chemical moieties that are designed capable of targeting and/or penetrating cells or other targets of interest and further capable of binding therapeutic agen
The present invention relates to a novel delivery system for delivering therapeutic agents into living cells, and more particularly, to novel chemical moieties that are designed capable of targeting and/or penetrating cells or other targets of interest and further capable of binding therapeutic agents to be delivered to these cells, and to delivery systems containing same.
대표청구항▼
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
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; andp 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 Z1 and Z2 is independently a reactive group capable of binding a biologically active moiety; or a hydrogen atom, provided that at least one of Z1 and Z2 is a reactive group wherein said reactive group is hydroxy, amine, halide, a phosphorous-containing group, —NH—CO—NH2, —NH—CS—NH2 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; andq 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 Z1 and Z2 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 Z1 and Z2 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 Z1 and Z2 is independently a reactive group capable of binding a biologically active moiety; or a hydrogen atom, provided that at least one of Z1 and Z2 is a reactive group wherein said reactive group is hydroxy, amine, halide, a phosphorous-containing group, —NH—CO—NH2, —NH—CS—NH2 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; andeach 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 Z1 and Z2 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 Z1 and Z2 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): whereineach of T1 and T2 is independently a biologically active moiety or absent, wherein at least one of T1 and T2 is present; and wherein said biologically active substance is a therapeutically active agent, a labeling moiety, or combination thereof;each of Z1′, Z2′, is independently a derivative of Z1 and Z2 , respectively, as a result of binding the biologically active group, wherein said Z1 and Z2 reactive group is hydroxyl, amine, halide, a phosphorous-containing group, a phosphate, C-amide, N-amide, thiol or COOH; andY 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; andq is an integer between 0 and 10;wherein if T1 or T2 is absent then Z1′ or Z2′ connected to it is replaced with Z1 or Z2 respectively. 16. The conjugate according to claim 15, defined by the structure of formula IV(h): wherein T1, T2, Z1′ and Z2′ 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 T1 and T2 is independently a biologically active moiety or absent, wherein at least one of T1 and T2 is present; and wherein said biologically active substance is a therapeutically active agent, a labeling moiety, or combination thereof;each of Z1′, Z2′, is independently a derivative of Z1 and Z2 , respectively, as a result of binding the biologically active group,wherein said Z1 and Z2 is independently a reactive group capable of binding a biologically active moiety; or a hydrogen atom, provided that at least one of Z1 and Z2 is a reactive group wherein said reactive group is hydroxy, amine, halide, a phosphorous-containing group, —NH—CO—NH2, —NH—CS—NH2C-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; andeach of r and r′ is independently an integer number of between 1 and 50;wherein if T1 or T2 is absent then Z1 ′ or Z2′ , is replaced with Z1 or Z2 respectively. 19. The conjugate according to claim 18, defined by the structure of formula IV(a): wherein T1, T2, Z1′ and Z2′ 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.
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