Targeted delivery of controlled release polymer systems

• US 20050037075A1
• Filed: 06/04/2004
• Published: 02/17/2005
• Est. Priority Date: 06/06/2003
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Farokhzad, Omid C., Langer, Robert S., Jon, Sangyong
• Granted Patent: US 7,550,441 B2
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 48/0041 the non-active part being polymeric
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: Y10S 530/817 Entrapped within the carrier, e.g. gel, hollow fibre

Abstract

The present invention relates to a conjugate that includes a nucleic acid ligand bound to a controlled release polymer system, a pharmaceutical composition that contains the conjugate, and methods of treatment using the conjugate. The controlled release polymer system includes an agent such as a therapeutic, diagnostic, prognostic, or prophylactic agent. The nucleic acid ligand that is bound to the controlled release polymer system, binds selectively to a target, such as a cell surface antigen, and thereby delivers the controlled release polymer system to the target.

Claims

1. A conjugate, comprising a nucleic acid ligand bound to a controlled release polymer system.

2. The conjugate of claim 1, wherein the controlled release polymer system comprises a polymer that is biologically degradable, chemically degradable, or both biologically and chemically degradable.

3. The conjugate of claim 2, wherein the controlled release polymer system comprises a polymer selected from the group consisting of poly(lactic acid), derivatives of poly(lactic acid), PEGylated poly(lactic acid), poly(lactic-co-glycolic acid), derivatives of poly(lactic-co-glycolic acid), PEGylated poly(lactic-co-glycolic acid), a polyanhydride, poly(ortho esters), derivaties of poly(ortho esters), PEGylated poly(ortho esters) poly(caprolactone), derivatives of poly(caprolactone), PEGylated poly(caprolactone, polylysine, derivatives of polylysine, PEGylated polylysine, poly(ethylene imine), derivatives of poly(ethylene imine), PEGylated poly(ethylene imine), poly(acrylic acid), derivatives of poly(acrylic acid), poly(urethane), derivatives of poly(urethane), and combinations thereof.

4. The conjugate of claim 2, wherein the controlled release polymer system is a microsphere or a nanosphere.

5. The conjugate of claim 1, wherein the nucleic acid ligand is selected from the group consisting of a DNA, a RNA, a modified DNA, a modified RNA and combinations thereof.

6. The conjugate of claim 1, wherein the nucleic acid ligand comprises one or more modified nucleotide and is resistant to endonuclease degradation, exonuclease degradation or both endo- and exonuclease degradation.

7. The conjugate of claim 6, wherein the nucleic acid ligand is prepared using L-enaniomeric nucleosides.

8. The conjugate of claim 5, wherein one or more internal nucleotides at the 3′

-end, 5′

-end or both at the 3′

- and 5′

-end of the nucleic acid ligand is inverted to yield a 3′

-3′

or a 5′

-5′

nucleotide linkage.

9. The conjugate of claim 5, wherein one or more of the nucleotides of the nucleic acid ligand are bound to another nucleotide by a hydrocarbon linker or a polyether linker.

10. The conjugate of claim 1, wherein the nucleic acid ligand binds selectively to a cell surface antigen.

11. The conjugate of claim 1, wherein the nucleic acid ligand binds to a protein, a carbohydrate, or a nucleic acid.

12. The conjugate of claim 11, wherein the nucleic acid ligand binds to a protein selected from the group consisting of tumor-markers, integrins, cell surface receptors, transmembrane proteins, ion channels, membrane transport protein, enzymes, antibodies, and chimeric proteins.

13. The conjugate of claim 11, wherein the nucleic acid ligand binds to a carbohydrate selected from the group consisting of glycoproteins, sugar residues and glycocalyx.

14. The conjugate of claim 11, wherein the nucleic acid ligand binds to a nucleic acid selected from the group consisting of DNA, RNA, modified DNA, modified RNA and combinations thereof.

15. The conjugate of claim 1, wherein the nucleic acid ligand binds to a cell during a specific developmental stage or to a cell in a specific disease state.

16. The conjugate of claim 15 wherein the cell in a specific developmental stage has developmentally specific cell surface antigens.

17. The conjugate of claim 15, wherein the cell in a specific disease state is a tumor cell that has tumor-associated antigens or tumor-specific antigens.

18. The conjugate of claim 1, further comprising an agent for localization.

19. The conjugate of claim 18, wherein the localizing agent is a magnetic particle.

20. The conjugate of claim 1, wherein the controlled release polymer system releases a therapeutic agent.

21. The conjugate of claim 20, wherein the therapeutic agent is selected from the group consisting of small molecule drugs, protein drugs, nucleic acid based drugs, and combinations thereof.

22. The conjugate of claim 21, wherein the therapeutic agent is a small molecule drug selected from the group consisting of an antibiotic, an antiviral, an antiparasitic agent, an anti-cancer agent, a radionuclide, an anticoagulant, an analgesic agent, an anesthetic agent, an ion channel potentiator, and ion channel inhibitor, an anti-inflammatory and combinations thereof.

23. The conjugate of claim 21, wherein the therapeutic agent is a protein drug selected from the group consisting of an antibody, an antibody fragment, a recombinant antibody, a recombinant protein, a purified protein, a peptide, an amino acid and combinations thereof.

24. The conjugate of claim 21, wherein the therapeutic agent is a nucleic acid based drug selected from the group consisting of DNA, RNA, modified DNA, modified RNA, antisense oligonucleotides, expression plasmid systems, intact genes, intact or partially complementary DNA promotor regions of gene expression, intact or partially complementary DNA repressor regions of gene expression, intact or partially complementary DNA enhancer regions of gene expression, nucleotides, modified nucleotides, nucleosides, modified nucleosides, nucleic acid ligands, and combinations thereof.

25. The conjugate of claim 20, wherein the polymer particle comprises PEGylated polyethyleneimine or PEGylated polylysine, and the therapeutic agent is anionic.

26. The conjugate of claim 25, wherein the therapeutic agent is heparin or a nucleic acid.

27. The conjugate of claim 1, wherein the controlled release polymer system releases a diagnostic or prognostic agent.

28. The conjugate of claim 27, wherein the diagnostic or prognostic agent is a radionuclide.

29. The conjugate of claim 28, wherein the radionuclide is selected from the group consisting of ¹²³I, ¹²⁵I, ¹³⁰I, ¹³¹I, ¹³⁵I, ⁴⁷Sc, ⁷²As, ⁷²Se, ⁹⁰Y, ⁸⁸Y, ⁹⁷Ru, ¹⁰⁰Pd, ^101mRh, ¹¹⁹Sb, ¹²⁸Ba, ¹⁹⁷Hg, ²¹¹At, ²¹²Bi, ²¹²Pb, ¹⁰⁹Pd, ¹¹¹In, ⁶⁷Ga, ⁶⁸Ga, ⁶⁷Cu, ⁷⁵Br, ⁷⁷Br, ^99mTc, ¹⁴C, ¹³N, 15O, ³²P, ³³P and ¹⁸F.

30. The conjugate of claim 27, wherein the diagnostic or prognostic agent is a fluorescent molecule.

31. The method of claim 27, wherein the diagnostic or prognostic agent is an iron oxide particle.

32. The method of claim 27, wherein the diagnostic or prognostic agent is a gadolinium complex.

33. The conjugate of claim 1, wherein the controlled release polymer system releases a prophylactic agent.

91. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a conjugate of claim 1, 4, 18, 20, or 27.

34. A method of delivering an agent to a target cell, comprising contacting the target cell with a conjugate comprising a nucleic acid ligand bound to a controlled release polymer system that comprises the agent, wherein the nucleic acid ligand selectively binds to the target cell.

35. The method of claim 34, wherein the controlled release polymer system comprises a polymer that is biologically degradable, chemically degradable or both biologically and chemically deradable.

36. The method of claim 35, wherein the controlled release polymer system comprises a polymer selected from the group consisting of poly(lactic acid), derivatives of poly(lactic acid), PEGylated poly(lactic acid), poly(lactic-co-glycolic acid), derivatives of poly(lactic-co-glycolic acid), PEGylated poly(lactic-co-glycolic acid), a polyanhydride, poly(ortho esters), derivatives of pholy(ortho esters), PEGylated poly(ortho esters), poly(caprolactone), derivatives of poly(caprolactone, PEGylated poly(caprolactone, polylysine, derivatives of polylysine, PEGylated polylysine, poly(ethylene imine), derivatives of poly(ethylene imine), PEGylated poly(ethylene imine), poly(acrylic acid), derivatives of poly(acrylic acid), poly(urethane), derivatives of poly(urethane), and combinations thereof.

37. The method of claim 35, wherein the controlled release polymer system is a microsphere or a nanosphere.

38. The method of claim 34, wherein the nucleic acid ligand is selected from the group consisting of a DNA, a RNA, a modified DNA, a modified RNA and combinations thereof.

39. The method of claim 34, wherein the nucleic acid ligand comprises one or more modified nucleotide and is resistant to endonuclease degradation, exonuclease degradation or both endo- and exonuclease degradation.

40. The method of claim 39, wherein the nucleic acid ligand is prepared using L-enantiomer nucleosides.

41. The method of claim 38, wherein one or more internal nucleotides at the 3′

-end, 5′

-end or both at the 3′

- and 5′

-end of the nucleic acid ligand is inverted to yield a 3′

-3′

or a 5′

-5′

nucleotide linkage.

42. The conjugate of claim 38, wherein one or more of the nucleotides of the nucleic acid ligand are bound to another nucleotide by a hydrocarbon linker or a polyether linker.

43. The method of claim 34, wherein the nucleic acid ligand binds selectively to a cell surface antigen.

44. The method of claim 43, wherein the nucleic acid ligand binds to a protein, a carbohydrate or a nucleic acid.

45. The method of claim 44, wherein the nucleic acid ligand binds to a protein selected from the group consisting of tumor-markers, integrins, cell surface receptors, transmembrarne proteins, ion channels, membrane transport protein, enzymes, antibodies, and chimeric proteins.

46. The method of claim 44, wherein the nucleic acid ligand binds to a carbohydrate selected from the group consisting of glycoproteins, sugar residues and glycocalyx.

47. The method of claim 44, wherein the nucleic acid ligand binds to a nucleic acid selected from the group consisting of DNA, RNA, modified DNA, modified RNA and combinations thereof.

48. The method of claim 34, wherein the conjugate further comprises an agent for localization.

49. The method of claim 48, wherein the localizing agent is a magnetic particle and the target tissue is contacted with the conjugate by placing the target tissue in a magnetic field.

50. The method of claim 34, wherein the controlled release polymer system releases a therapeutic agent.

51. The method of claim 40, wherein the therapeutic agent is selected from the group consisting of small molecule drugs, protein drugs, nucleic acid based drugs, and combinations thereof.

52. The method of claim 51, wherein the therapeutic agent is a small molecule drug selected from the group consisting of an antibiotic, an antiviral, an antiparasitic agent, an anti-cancer agent, a radionuclide, an anticoagulant, an analgesic agent, an anesthetic agent, an ion channel potentiator, and ion channel inhibitor, an anti-inflammatory and combinations thereof.

53. The method of claim 51, wherein the therapeutic agent is a protein drug selected from the group consisting of an antibody, an antibody fragment, a recombinant antibody, a recombinant protein, a purified protein, a peptide, an amino acid and combinations thereof.

54. The method of claim 51, wherein the therapeutic agent is a nucleic acid based drug selected from the group consisting of DNA, RNA, modified DNA, modified RNA, antisense oligonucleotides, expression plasmid systems, intact genes, intact or partially complementary DNA promotor regions of gene expression, intact or partially complementary DNA repressor regions of gene expression, intact or partially complementary DNA enhancer regions of gene expression, nucleotides, modified nucleotides, nucleosides, modified nucleosides, nucleic acid ligans, and combinations thereof.

55. The method of claim 50, wherein the polymer particle comprises polyethyleneimine or poly(lysine), and the therapeutic agent is anionic.

56. The method of claim 55, wherein the therapeutic agent is heparin or a nucleic acid.

57. The method of claim 34, wherein the controlled release polymer system releases a diagnostic or prognostic agent.

58. The method of claim 57, wherein the diagnostic or prognostic agent is a radionuclide.

59. The method of claim 58, wherein the radionuclide is selected from the group consisting of ¹²³I, ¹²⁵I, ¹³⁰I, ¹³¹I, ¹³⁵I, ⁴⁷Sc, ⁷²As, ⁷²Se, ⁹⁰Y, ⁸⁸Y, ⁹⁷Ru, ¹⁰⁰Pd, ^101mRh, ¹¹⁹Sb, ¹²⁸Ba, ¹⁹⁷Hg, ²¹¹At, ²¹²Bi, ²¹²Pb, ¹⁰⁹Pd, ¹¹¹In, ⁶⁷Ga, ⁶⁸Ga, ⁶⁷Cu, ⁷⁵Br, ⁷⁷Br, ^99mTc, ¹⁴C, ¹³N, 15O, ³²P, ³³P and ¹⁸F.

60. The method of claim 57, wherein the diagnostic or prognostic agent is a iron oxide particle.

61. The method of claim 57, wherein the diagnostic or prognostic agent is a is a gadolinium complex.

62. The method of claim 34, wherein the controlled release polymer system releases a prophylactic agent.

63. A method of diagnosing, predicting the outcome, or treating a patient with cancer, comprising administering to the patient a conjugate comprising a nucleic acid ligand bound to a controlled release polymer system, wherein the nucleic acid ligand selectively binds to tumor cells.

64. The method of claim 63, wherein the controlled release polymer system comprises a polymer that is biologically degradable, chemically degradable, or both biologically and chemically degradable.

65. The method of claim 64, wherein the controlled release polymer system comprises a polymer selected from the group consisting of poly(lactic acid), derivatives of poly(lactic acid), PEGylated poly(lactic acid), poly(lactic-co-glycolic acid), derivatives of poly(lactic-co-glycolic acid), PEGylated poly(lactic-co-glycolic acid), a polyanhydride, poly(caprolactone), derivatives of poly(caprolactone, PEGylated poly(caprolactone, polylysine, derivatives of polylysine, PEGylated polylysine, poly(ethylene imine), derivatives of poly(ethylene imine), PEGylated poly(ethylene imine), poly(acrylic acid), derivatives of poly(acrylic acid), poly(urethane), derivatives of poly(urethane), and combinations thereof.

66. The method of claim 64, wherein the controlled release polymer system is a microsphere or a nanosphere.

67. The method of claim 63, wherein the nucleic acid ligand is selected from the group consisting of a DNA, a RNA, a modified DNA, a modified RNA and combinations thereof.

68. The method of claim 63, wherein the nucleic acid ligand comprises one or more modified nucleotide and is resistant to endonuclease degradation, exonuclease degradation or both endo- and exonuclease degradation.

69. The method of claim 68, wherein the nucleic acid ligand is prepared using L-enantiomer nucleosides.

70. The method of claim 67, wherein one or more internal nucleotides at the 3′

-end, 5′

-end or both at the 3′

- and 5′

-end of the nucleic acid ligand is inverted to yield a 3′

-3′

or a 5′

-5′

nucleotide linkage.

71. The conjugate of claim 67, wherein one or more of the nucleotides of the nucleic acid ligand are bound to another nucleotide by a hydrocarbon linker or a polyether linker.

72. The method of claim 63, wherein the nucleic acid ligand binds selectively to a cell surface antigen.

73. The method of claim 63, wherein the nucleic acid ligand binds to a protein, a carbohydrate, or a nucleic acid.

74. The method of claim 73, wherein the nucleic acid ligand binds to a protein selected from the group consisting of tumor-markers, integrins, cell surface receptors, transmembrarne proteins, ion channels, membrane transport protein, enzymes, antibodies, and chimeric proteins.

75. The method of claim 73, wherein the nucleic acid ligand binds to a carbohydrate selected from the group consisting of glycoproteins, sugar residues and glycocalyx.

76. The method of claim 73, wherein the nucleic acid ligand binds to a nucleic acid selected from the group consisting of DNA, RNA, modified DNA, modified RNA and combinations thereof.

77. The method of claim 63, wherein the conjugate further comprises an agent for localization.

78. The method of claim 77, wherein the localizing agent is a magnetic particle and the tumor tissue is placed in a magnetic field.

79. The method of claim 63, wherein the controlled release polymer system releases a therapeutic agent.

80. The method of claim 79, wherein the therapeutic agent is selected from the group consisting of small molecule drugs, protein drugs, nucleic acid based drugs, and combinations thereof.

81. The method of claim 80, wherein the therapeutic agent is a small molecule drug selected from the group consisting of an antibiotic, an antiviral, an antiparasitic agent, an anti-cancer agent, a radionuclide, an anticoagulant, an analgesic agent, an anesthetic agent, an ion channel potentiator, and ion channel inhibitor, an anti-inflammatory and combinations thereof.

82. The method of claim 80, wherein the therapeutic agent is a protein drug selected from the group consisting of an antibody, an antibody fragment, a recombinant antibody, a recombinant protein, a purified protein, a peptide, an amino acid and combinations thereof.

83. The conjugate of claim 80, wherein the therapeutic agent is a nucleic acid based drug selected from the group consisting of DNA, RNA, modified DNA, modified RNA, antisense oligonucleotides, expression plasmid systems, intact genes, intact or partially complementary DNA promotor regions of gene expression, intact or partially complementary DNA repressor regions of gene expression, intact or partially complementary DNA enhancer regions of gene expression, nucleotides, modified nucleotides, nucleosides, modified nucleosides, nucleic acid ligans, and combinations thereof.

84. The method of claim 63, wherein the polymer system releases a diagnostic or prognostic agent.

85. The method of claim 84, wherein the diagnostic or prognostic agent is a radionuclide.

86. The method of claim 85, wherein the radionuclide is selected from the group consisting of ¹²³I, ¹²⁵I, ¹³⁰I, ¹³¹I, ¹³⁵I, ⁴⁷Sc, ⁷²As, ⁷²Se, ⁹⁰Y, ⁸⁸Y, ⁹⁷Ru, ¹⁰⁰Pd, ^101mRh, ¹¹⁹Sb, ¹²⁸Ba, ¹⁹⁷Hg, ²¹¹At, ²¹²Bi, ²¹²Pb, ¹⁰⁹Pd, ¹¹¹In, ⁶⁷Ga, ⁶⁸Ga, ⁶⁷Cu, ⁷⁵Br, ⁷⁷Br, ^99mTc, ¹⁴C, ¹³N, 15O, ³²P, ³³P and ¹⁸F.

87. The method of claim 84, wherein the diagnostic or prognostic agent is an iron oxide particle.

88. The method of claim 84, wherein the diagnostic or prognostic agent is a gadolinium complex.

89. The method of claim 84, wherein the diagnostic agent is a fluorescent molecule.

90. The method of claim 63, wherein the controlled release polymer system releases a prophylactic agent.