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05/25/06 - USPTO Class 514 | 78 views | #20060111274 | Prev - Next | About this Page

Methods and compositions for enhancing transport across biological membranes

Title: Methods and compositions for enhancing transport across biological membranes

Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai

Brief Patent Description - Full Patent Description - Patent Claims

The Patent Description & Claims data below is from USPTO Patent Application 20060111274, Methods and compositions for enhancing transport across biological membranes.

1. A conjugate comprised of a biologically active agent covalently attached to a polymeric carrier having a non-peptide backbone composed of from about 6 to about 25 subunits, at least 50% of which are substituted with a guanidino or amidino sidechain moiety, wherein adjacent subunits are linked through a covalent linkage selected from amido, N-substituted amido, ester, methylenecarbonyl, methyleneimino, thioamido, phosphinate, phosphonamidate, phosphonamidate ester, retropeptidyl, trans-alkenyl, fluoroalkenyl, ethylene, thioether, hydroxyethylene, methyleneoxy, tetrazolyl, retrothiamido, retromethyleneimino, sulfonamido, methylenesulfonamido, retrosulfonamido, alkylene, sulfonyl, azo, and imino linkages, and combinations thereof, with the proviso that when the subunits are amino acids, the covalent linkages are other than amido linkages.

2. The conjugate of claim 1, wherein the subunits are selected from N-substituted amino acids, hydroxy amino acids, and amino aldehydes.

3. The conjugate of claim 2, wherein the polymeric carrier is composed of 7 to 15 subunits.

4. The conjugate of claim 3, wherein the subunits are N-substituted amino acids.

5. The conjugate of claim 4, wherein the subunits are N-substituted glycine residues.

6. The conjugate of claim 5, wherein adjacent subunits are linked through N-substituted amide linkages, such that the polymeric carrier is a peptoid.

7. The conjugate of claim 6, wherein the polymeric carrier is composed of 7 to 15 N-substituted glycine residues.

8. The conjugate of claim 4, wherein the N-substituted amino acids are N-substituted arginine residues.

9. The conjugate of claim 8, wherein at least one of the N-substituted arginine residues has a D-configuration.

10. The conjugate of claim 9, wherein all of the N-substituted arginine residues have a D-configuration.

11. The conjugate of claim 8, wherein the polymeric carrier is composed of 7 to 15 N-substituted arginine residues.

12. The conjugate of claim 1, wherein the carrier is effective to increase the rate at which the conjugated biologically active agent is transported through a biological membrane relative to the rate at which the biologically active agent can be transported through the biological membrane in unconjugated form.

13. The conjugate of claim 1, wherein the carrier is effective to increase the amount of conjugated biologically active agent that is transported through a biological membrane relative to the amount of biologically active agent that can be transported through the biological membrane in unconjugated form.

14. The conjugate of claim 1, wherein the carrier is effective to increase the rate at which the conjugate is transported through a biological membrane relative to the rate at which the biologically active agent conjugated to a basic HIV tat peptide consisting of residues 49-57 can be transported through the biological membrane.

15. The conjugate of claim 1, wherein at least 70% of the subunits contain a guanidino or amidino sidechain moiety.

16. The conjugate of claim 15, wherein at least 90% of the subunits contain a guanidino or amidino sidechain moiety.

17. The conjugate of claim 16, wherein all of the subunits contain a guanidino or amidino sidechain7moiety.

18. The conjugate of claim 1, wherein the polymeric carrier includes at least 6 contiguous subunits substituted with guanidino sidechain moieties.

19. The conjugate of claim 1, wherein the guanidino sidechain moieties have the structure and the amidino sidechain moieties have the structure wherein n is 2, 3, 4 or 5.

20. The conjugate of claim 19, wherein n is 3.

21. The conjugate of claim 1, wherein the biologically active agent is covalently attached to the polymeric carrier through a linker.

22. The conjugate of claim 21, wherein the linker contains a linkage that is chemically or enzymatically cleaved in vivo.

23. The conjugate of claim 22, wherein the linkage is a carbamate, ester, thioether, disulfide or hydrazone linkage.

24. The conjugate of claim 1, wherein the polymeric carrier is attached on at least one terminus to a flanking moiety that does not significantly affect the delivery of the biologically active agent across biological membranes.

25. The conjugate of claim 22, wherein the polymeric carrier is attached on at least one terminus to a flanking moiety that does not significantly affect the delivery of the biologically active agent across biological membranes.

26. The conjugate of claim 25, wherein the polymeric carrier has a first terminus and a second terminus, with the first terminus attached to a first flanking moiety and the second terminus conjugated to the biologically active agent through the linker.

27. The conjugate of claim 26, wherein a second flanking moiety is attached to the second terminus, such that the linker is attached to the second flanking moiety.

28. The conjugate of claim 26, wherein the first flanking moiety comprises one or more subunits that do not contain said guanidino sidechain or said amidino sidechain.

29. The conjugate of claim 27, wherein the first flanking moiety and the second flanking moiety comprise one or more subunits that do not contain said guanidino sidechain or said amidino sidechain.

30. The conjugate of claim 26, wherein the first flanking moiety is a blocking group effective to prevent ubiquitination in vivo.

31. The conjugate of claim 30, wherein the blocking group is an acetyl or benzyl group.

32. The conjugate of claim 1, wherein the biologically active agent is a therapeutic compound whose efficacy in non-conjugated form is limited by its solubility in aqueous liquid or its inability to cross biological membranes to manifest biological activity.

33. The conjugate of claim 1, wherein the biologically active agent is an antimicrobial agent.

34. The conjugate of claim 1, wherein the biologically active agent is an anticancer agent.

35. The conjugate of claim 1, wherein the biologically active agent is comprised of a metal.

36. The conjugate of claim 1, wherein the biologically active agent is a macromolecule.

37. The conjugate of claim 36, wherein the macromolecule is selected from the group consisting of nucleic acids, oligonucleotides, polynucleotides, peptides, proteins, peptide nucleic acids, and polysaccharides.

38. The conjugate of claim 37, wherein the macromolecule is a protein.

39. The conjugate of claim 38, wherein the protein is an enzyme, an antigen, an antibody, or an antibody fragment.

40. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.

41. A pharmaceutical composition for administration, to a human subject, of a biologically active agent whose efficacy in non-conjugated form is limited by its aqueous solubility, said composition comprising the conjugate of claim 32 and a pharmaceutically acceptable carrier.

42. A method for enhancing transport of a selected biologically active agent across a biological membrane, comprising contacting a biological membrane with a conjugate comprised of the biologically active agent and a polymeric carrier covalently attached thereto, wherein the polymeric carrier has a non-peptide backbone composed of from about 6 to about 25 subunits, at least 50% of which are substituted with a guanidino or amidino sidechain moiety, wherein adjacent subunits are linked through a covalent linkage selected from amido, N-substituted amido, ester, methylenecarbonyl, methyleneimino, thioamido, phosphinate, phosphonamidate, phosphonamidate ester, retropeptidyl, trans-alkenyl, fluoroalkenyl, ethylene, thioether, hydroxyethylene, methyleneoxy, tetrazolyl, retrothiamido, retromethyleneimino, sulfonamido, methylenesulfonamido, retrosulfonamido, alkylene, sulfonyl, azo, and imino linkages, and combinations thereof, with the proviso that when the subunits are amino acids, the covalent linkages are other than amido linkages.

43. The method of claim 42, wherein the subunits are selected from N-substituted amino acids, hydroxy amino acids, and amino aldehydes.

44. The method of claim 43, wherein the biological membrane is a eukaryotic cell membrane.

45. The method of claim 44, wherein the biological membrane is a prokaryotic cell membrane.

46. A conjugate comprised of a biologically active agent covalently attached to a polymeric carrier having a non-peptide, non-peptoid, backbone composed of from about 6 to about 25 subunits, at least 50% of which are substituted with a guanidino or amidino sidechain moiety, wherein adjacent subunits are linked through a covalent linkage selected from amido, N-substituted amido, ester, methylenecarbonyl, methyleneimino, thioamido, phosphinate, phosphonamidate, phosphonamidate ester, retropeptidyl, trans-alkenyl, fluoroalkenyl, ethylene, thioether, hydroxyethylene, methyleneoxy, tetrazolyl, retrothiamido, retromethyleneimino, sulfonamido, methylenesulfonamido, retrosulfonamido, alkylene, sulfonyl, azo, and imino linkages, and combinations thereof.

47. The conjugate of claim 46, wherein the sidechain moieties are selected from amino acid sidechain moieties, N-substituted amino acid sidechain moieties, hydroxy amino acid sidechain moieties, and amino aldehyde sidechain moieties.

48. The conjugate of claim 47, wherein the polymeric carrier is composed of 7 to 15 subunits.

49. The conjugate of claim 48, wherein the sidechain moieties are N-substituted amino acid sidechain moieties.

50. The conjugate of claim 48, wherein the sidechain moieties are amino acid sidechain moieties.

51. The conjugate of claim 50, wherein the polymeric carrier is composed of 7 to 15 subunits having sidechains composed of amino acid sidechain moieties.

52. The conjugate of claim 50, wherein the amino acid sidechain moieties are arginine sidechain moieties.

53. The conjugate of claim 52, wherein at least one of the arginine sidechain moieties has a D-configuration.

54. The conjugate of claim 53, wherein all of the arginine sidechain moieties have a D-configuration.

55. The conjugate of claim 52, wherein the polymeric carrier is composed of 7 to 15 subunits having sidechains composed of arginine sidechain moieties.

56. The conjugate of claim 46, wherein the carrier is effective to increase the rate at which the conjugated biologically active agent is transported through a biological membrane relative to the rate at which the biologically active agent can be transported through the biological membrane in unconjugated form.

57. The conjugate of claim 46, wherein the carrier is effective to increase the amount of conjugated biologically active agent that is transported through a biological membrane relative to the amount of biologically active agent that can be transported through the biological membrane in unconjugated form.

58. The conjugate of claim 46, wherein the carrier is effective to increase the rate at which the conjugate is transported through a biological membrane relative to the rate at which the biologically active agent conjugated to a basic HIV tat peptide consisting of residues 49-57 can be transported through the biological membrane.

59. The conjugate of claim 46, wherein at least 70% of the subunits contain a guanidino or amidino sidechain moiety.

60. The conjugate of claim 59, wherein at least 90% of the subunits contain a guanidino or amidino sidechain moiety.

61. The conjugate of claim 60, wherein all of the subunits contain a guanidino or amidino sidechain moiety.

62. The conjugate of claim 46, wherein the polymeric carrier includes at least 6 contiguous subunits having guanidino sidechain moieties.

63. The conjugate of claim 46, wherein the guanidino sidechain moieties have the structure and the amidino sidechain moieties have the structure wherein n is 2, 3, 4 or 5.

64. The conjugate of claim 65, wherein n is 3.

65. The conjugate of claim 46, wherein the biologically active agent is covalently attached to the polymeric carrier through a linker.

66. The conjugate of claim 65, wherein the linker contains a linkage that is chemically or enzymatically cleaved in vivo.

67. The conjugate of claim 66, wherein the linkage is a carbamate, ester, thioether, disulfide, or hydrazone linkage.

68. The conjugate of claim 46, wherein the polymeric carrier is attached on at least one terminus to a flanking moiety that does not significantly affect the delivery of the biologically active agent across biological membranes.

69. The conjugate of claim 66, wherein the polymeric carrier is attached on at least one terminus to a flanking moiety that does not significantly affect the delivery of the biologically active agent across biological membranes.

70. The conjugate of claim 69, wherein the polymeric carrier has a first terminus and a second terminus, with the first terminus attached to a first flanking moiety and the second terminus conjugated to the biologically active agent through the linker.

71. The conjugate of claim 70, wherein a second flanking moiety is attached to the second terminus, such that the linker is attached to the second flanking moiety.

72. The conjugate of claim 70, wherein the first flanking moiety comprises one or more subunits that do not contain said guanidino sidechain moiety or said amidino sidechain moiety.

73. The conjugate of claim 71, wherein the first flanking moiety and the second flanking moiety comprise one or more subunits that do not contain said guanidino sidechain moiety or said amidino sidechain moiety.

74. The conjugate of claim 70, wherein the first flanking moiety is a blocking group effective to prevent ubiquitination in vivo.

75. The conjugate of claim 74, wherein the blocking group is an acetyl or benzyl group.

76. The conjugate of claim 46, wherein the biologically active agent is a therapeutic compound whose efficacy in non-conjugated form is limited by its solubility in aqueous liquid or its inability to cross biological membranes to manifest biological activity.

77. The conjugate of claim 46, wherein the biologically active agent is an antimicrobial agent.

78. The conjugate of claim 46, wherein the biologically active agent is an anticancer agent.

79. The conjugate of claim 46, wherein the biologically active agent is comprised of a metal.

80. The conjugate of claim 46, wherein the biologically active agent is a macromolecule.

81. The conjugate of claim 80, wherein the macromolecule is selected from the group consisting of nucleic acids, oligonucleotides, polynucleotides, peptides, proteins, peptide nucleic acids, and polysaccharides.

82. The conjugate of claim 81, wherein the macromolecule is a protein.

83. The conjugate of claim 82, wherein the protein is an enzyme, an antigen, an antibody, or an antibody fragment.

84. A pharmaceutical composition comprising the conjugate of claim 46 and a pharmaceutically acceptable carrier.

85. A pharmaceutical composition for administration, to a human subject, of a biologically active agent whose efficacy in non-conjugated form is limited by its aqueous solubility, said composition comprising the conjugate of claim 76 and a pharmaceutically acceptable carrier.

86. A method for enhancing transport of a selected biologically active agent across a biological membrane, comprising contacting a biological membrane with a conjugate comprised of the biologically active agent and a polymeric carrier covalently attached thereto, wherein the polymeric carrier has a non-peptide, non-peptoid, backbone composed of from about 6 to about 25 subunits, at least 50% of which are substituted with a guanidino or amidino sidechain moiety, wherein adjacent subunits are linked through a covalent linkage selected from amido, N-substituted amido, ester, methylenecarbonyl, methyleneimino, thioamido, phosphinate, phosphonamidate, phosphonamidate ester, retropeptidyl, trans-alkenyl, fluoroalkenyl, ethylene, thioether, hydroxyethylene, methyleneoxy, tetrazolyl, retrothiamido, retromethyleneimino, sulfonamido, methylenesulfonamido, retrosulfonamido, alkylene, sulfonyl, azo, and imino linkages, and combinations thereof.

87. The method of claim 86, wherein the sidechain moieties are selected from amino acid sidechain moieties, N-substituted amino acid sidechain moieties, hydroxy amino acid sidechain moieties, and amino aldehyde sidechain moieties.

88. The method of claim 87, wherein the biological membrane is a eukaryotic cell membrane.

89. The method of claim 87, wherein the biological membrane is a prokaryotic cell membrane.

Brief Patent Description - Full Patent Description - Patent Claims

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