Dendrimer Based Compositions And Methods Of Using The Same

• US 20090104119A1
• Filed: 08/25/2005
• Published: 04/23/2009
• Est. Priority Date: 08/25/2004
• Status: Abandoned Application

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Cao, Zhengyi, Kukowska-Latallo, Jolanta F., Majoros, Istvan J., Baker, James R., Thomas, Thommey P.
• Application Number:
  US11/661,465
• Publication Number:
  US 20090104119A1
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 47/595 Polyamides, e.g. nylon polyamino acids A61K47/62
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 49/0041 Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal in vivo G01N
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C08G 73/0206 Polyalkylene(poly)amines
• CPC Class Codes: C08G 73/028 Polyamidoamines
• CPC Class Codes: C08G 83/003 Dendrimers

Abstract

The present invention relates to novel therapeutic and diagnostic dendrimers. In particular, the present invention is directed to dendrimer based multifunctional compositions and systems for use in disease diagnosis and therapy (e.g., cancer diagnosis and therapy). The compositions and systems comprise one or more components for targeting, imaging, sensing, and/or providing a therapeutic or diagnostic material and monitoring the response to therapy of a cell or tissue (e.g., a tumor).

Claims

1. A composition comprising a dendrimer, said dendrimer comprising a partially acetylated generation 5 (G5) polyamideamine (PAMAM), polypropylamine (POPAM), or PAMAM-POPAM dendrimer, said dendrimer comprising two or more reactive sites for conjugation of a functional group.

2. The composition of claim 1, wherein said dendrimer comprises two or more functional groups, wherein said functional groups are selected from the group consisting of a therapeutic agent, a targeting agent, an imaging agent, and a biological monitoring agent.

3. The composition of claim 2, wherein at least one of said functional groups is conjugated to said dendrimers via an ester bond.

4. The composition of claim 2, wherein said therapeutic agent comprises methotrexate.

5. The composition of claim 2, wherein said targeting agent comprises folic acid.

6. The composition of claim 2, wherein said targeting agent comprises an RGD peptide.

7. The composition of claim 2, wherein said imaging agent comprises a fluorescing agent.

8. The composition of claim 7, wherein said fluorescing agent comprises fluorescein isothiocyanate.

9. The composition of claim 7, wherein said fluorescing agent comprises 6-TAMARA.

10. The composition of claim 4, wherein said methotrexate is conjugated to said dendrimer via an ester bond.

11. The composition of claim 1, wherein said dendrimer comprises between 2 and 20 reaction sites.

12. The composition of claim 2, wherein said dendrimer is conjugated to said functional groups.

13. The composition of claim 12, wherein said conjugation comprises covalent bonds, ionic bonds, metallic bonds, hydrogen bonds, Van der Waals bonds, ester bonds or amide bonds.

14. The composition of claim 2, wherein said therapeutic agent comprises a chemotherapeutic agent, an anti-oncogenic agent, an anti-vascularizing agent, a tumor suppressor agent, an anti-microbial agent, or an expression construct comprising a nucleic acid encoding a therapeutic protein.

15. The composition of claim 14, wherein said therapeutic agent is protected with a protecting group.

16. The composition of claim 15, wherein said protecting group is selected from the group consisting of photo-labile protecting group, a radio-labile protecting group, and an enzyme-labile protecting group.

17. The composition of claim 1, wherein said dendrimer comprises a protected core diamine.

18. The composition of claim 1, wherein said reactive sites comprise primary amine groups.

19. A composition comprising a dendrimer, said dendrimer comprising a partially acetylated G5 PAMAM, POPAM, or PAMAM-POPAM dendrimer, said dendrimer further comprising one or more functional groups, said one or more functional groups selected from the group consisting of a therapeutic agent, a targeting agent, and an imaging agent.

20. The composition of claim 19, wherein said therapeutic agent comprises an anti-oncogenic agent.

21. The composition of claim 19, wherein said therapeutic agent comprises a chemotherapeutic agent.

22. The composition of claim 19, wherein said therapeutic agent comprises methotrexate.

23. The composition of claim 19, wherein said therapeutic agent comprises tritium.

24. The composition of claim 19, wherein said targeting agent comprises folic acid.

25. The composition of claim 19, wherein said targeting agent comprises an RGD peptide.

26. The composition of claim 19, wherein said imaging agent comprises a fluorescing agent.

27. The composition of claim 26, wherein said fluorescing agent comprises fluorescein isothiocyanate.

28. The composition of claim 26, wherein said fluorescing agent comprises 6-TAMARA.

29. The composition of claim 22, wherein said methotrexate is conjugated to said dendrimer via an ester bond.

30. The composition of claim 19, wherein said therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an anti-oncogenic agent, an anti-vascularizing agent, a tumor suppressor agent, an anti-microbial agent, and an expression construct comprising a nucleic acid encoding a therapeutic protein.

31. The composition of claim 19, wherein said therapeutic agent is protected with a protecting group.

32. The composition of claim 31, wherein said protecting group is selected from the group consisting of a photo-labile protecting group, a radio-labile protecting group, and an enzyme-labile protecting group.

33. The composition of claim 21, wherein said chemotherapeutic agent is selected from the group consisting of platinum complex, verapamil, podophylltoxin, carboplatin, procarbazine, mechloroethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, adriamycin, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, bleomycin, etoposide, tamoxifen, paclitaxel, taxol, transplatinum, 5-fluorouracil, vincristin, vinblastin, and methotrexate.

34. The composition of claim 20, wherein said anti-oncogenic agent comprises an antisense nucleic acid.

35. The composition of claim 34, wherein said antisense nucleic acid comprises a sequence complementary to an RNA of an oncogene.

36. The composition of claim 35, wherein said oncogene is selected from the group consisting of abl, Bcl-2, Bcl-xL, erb, fms, gsp, hst, jun, myc, neu, raf, ras, ret, src, and trk.

37. The composition of claim 30, wherein said nucleic acid encodes a protein selected from the group consisting of a tumor suppressor, a cytokine, a receptor, an inducer of apoptosis, and a differentiating agent.

38. The composition of claim 37, wherein said tumor suppressor is selected from the group consisting of BRCA1, BRCA2, C-CAM, p16, p21, p53, p73, Rb, and p27.

39. The composition of claim 37, wherein said cytokine is selected from the group consisting of GMCSF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN-β

, IFN-γ

, and TNF.

40. The composition of claim 37, wherein said receptor is selected from the group consisting of CFTR, EGFR, estrogen receptor, IL-2 receptor, and VEGFR.

41. The composition of claim 37, wherein said inducer of apoptosis is selected from the group consisting of AdE1B, Bad, Bak, Bax, Bid, Bik, Bim, Harakid, and ICE-CED3 protease.

42. The composition of claim 19, wherein said therapeutic agent comprises a short half-life radioisotope.

43. The composition of claim 19, wherein said imaging agent comprises a radioactive label selected from the group consisting of ¹⁴C, ³⁶C1, ⁵⁷Co, ⁵⁸Co, ⁵¹Cr, ¹²⁵I, ¹³¹I, ¹¹¹Ln, ¹⁵²Eu, ⁵⁹Fe, ⁶⁷Ga, ³²P, ¹⁸⁶Re, ³⁵S, ⁷⁵Se, Tc-99m, and ¹⁷⁵Yb.

44. The composition of claim 19, wherein said targeting agent is selected from the group consisting of an antibody, a receptor ligand, a hormone, a vitamin, and an antigen.

45. The composition of claim 44, wherein said antibody is specific for a disease specific antigen.

46. The composition of claim 45, wherein said disease specific antigen comprises a tumor specific antigen.

47. The composition of claim 44, wherein said receptor ligand is selected from the group consisting of a ligand for CFTR, a ligand for FGFR, a ligand for estrogen receptor, a ligand for FGR2, a ligand for folate receptor, a ligand for IL-2 receptor, a glycoprotein, a ligand for EGFR, and a ligand for VEGFR.

48. The composition of claim 44, wherein said receptor ligand is folic acid.

49. The composition of claim 44, wherein said receptor ligand is an RGD peptide.

50. A method of treating a disease comprising administering to a subject suffering from or susceptible to said disease a therapeutically effective amount of the composition of claim 19.

51. The method of claim 50, wherein said disease is a neoplastic disease.

52. The method of claim 51, wherein said neoplastic disease is selected from the group consisting of leukemia, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic, (granulocytic) leukemia, chronic lymphocytic leukemia, Polycythemia vera, lymphoma, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s disease, Multiple myeloma, Waldenstrom'"'"'s macroglobulinemia, Heavy chain disease, solid tumors, sarcomas and carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, uterine cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, and neuroblastomaretinoblastoma.

53. A method of altering tumor growth in a subject, comprising:

a) providing a composition comprising a dendrimer, said dendrimer comprising a partially acetylated G5 PAMAM, POPAM, or PAMAM-POPAM dendrimer, said dendrimer further comprising one or more functional groups, said one or more functional groups selected from the group consisting of a therapeutic agent, a targeting agent, and an imaging agent; and

b) administering said composition to said subject under conditions such that said tumor growth is altered.

54. The method of claim 53, wherein said altering comprises inhibiting tumor growth in said subject.

55. The method of claim 53, wherein said altering comprises reducing the size of said tumor in said subject.

56. The method of claim 53, wherein said composition comprising a dendrimer is co-administered with a chemotherapeutic agent or anti-oncogenic agent.

57. The method of claim 53 wherein said altering tumor growth sensitizes said tumor to chemotherapeutic or anti-oncogenic treatment.

58. The method of claim 53, wherein said therapeutic agent comprises an anti-oncogenic agent.

59. The method of claim 53, wherein said therapeutic agent comprises a chemotherapeutic agent.

60. The method of claim 53, wherein said therapeutic agent comprises methotrexate.

61. The method of claim 53, wherein said therapeutic agent comprises tritium.

62. The method of claim 53, wherein said targeting agent comprises folic acid.

63. The method of claim 53, wherein said targeting agent comprises an RGD peptide.

64. The method of claim 53, wherein said imaging agent comprises a fluorescing agent.

65. The method of claim 53, wherein said fluorescing agent comprises fluorescein isothiocyanate.

66. The method of claim 53, wherein said fluorescing agent comprises 6-TAMARA.

67. The method of claim 53, wherein said methotrexate is conjugated to said dendrimer via an ester bond.

68. The method of claim 53, wherein said therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an anti-oncogenic agent, an anti-vascularizing agent, a tumor suppressor agent, an anti-microbial agent, and an expression construct comprising a nucleic acid encoding a therapeutic protein.

69. The method of claim 53, wherein said therapeutic agent is protected with a protecting group.

70. The method of claim 69, wherein said protecting group is selected from the group consisting of a photo-labile protecting group, a radio-labile protecting group, and an enzyme-labile protecting group.

71. The method of claim 59, wherein said chemotherapeutic agent is selected from the group consisting of platinum complex, verapamil, podophylltoxin, carboplatin, procarbazine, mechloroethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, adriamycin, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, bleomycin, etoposide, tamoxifen, paclitaxel, taxol, transplatinum, 5-fluorouracil, vincristin, vinblastin, and methotrexate.

72. The method of claim 58, wherein said anti-oncogenic agent comprises an antisense nucleic acid.

73. The method of claim 72, wherein said antisense nucleic acid comprises a sequence complementary to an RNA of an oncogene.

74. The method of claim 73, wherein said oncogene is selected from the group consisting of abl, Bcl-2, Bcl-xL, erb, fins, gsp, hst, jun, myc, neu, raf, ras, ret, src, and trk.

75. The method of claim 68, wherein said nucleic acid encodes a protein selected from the group consisting of a tumor suppressor, a cytokine, a receptor, an inducer of apoptosis, and a differentiating agent.

76. The method of claim 75, wherein said tumor suppressor is selected from the group consisting of BRCA1, BRCA2, C-CAM, p16, p21, p53, p73, Rb, and p27.

77. The method of claim 75, wherein said cytokine is selected from the group consisting of GMCSF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN-β

, IFN-γ

, and TNF.

78. The method of claim 75, wherein said receptor is selected from the group consisting of CFTR, EGFR, estrogen receptor, IL-2 receptor, and VEGFR.

79. The method of claim 75, wherein said inducer of apoptosis is selected from the group consisting of AdE1B, Bad, Bak, Bax, Bid, Bik, Bim, Harakid, and ICE-CED3 protease.

80. The method of claim 53, wherein said therapeutic agent comprises a short half-life radioisotope.

81. The method of claim 53, wherein said imaging agent comprises a radioactive label selected from the group consisting of ¹⁴C, ³⁶Cl, ⁵⁷Co, ⁵⁸Co, ⁵¹Cr, ¹²⁵I, ¹³¹I, ¹¹¹Ln, ¹⁵²Eu, ⁵⁹Fe, ⁶⁷Ga, ³²P, ¹⁸⁶Re, ³⁵S, ⁷⁵Se, Tc-99m, and ¹⁷⁵Yb.

82. The method of claim 53, wherein said targeting agent is selected from the group consisting of an antibody, a receptor ligand, a hormone, a vitamin, and an antigen.

83. The method of claim 82, wherein said antibody is specific for a disease specific antigen.

84. The method of claim 83, wherein said disease specific antigen comprises a tumor specific antigen.

85. The method of claim 82, wherein said receptor ligand is selected from the group consisting of a ligand for CFTR, a ligand for FGFR, a ligand for estrogen receptor, a ligand for FGR2, a ligand for folate receptor, a ligand for IL-2 receptor, a glycoprotein, a ligand for EGFR, and a ligand for VEGFR.

86. The method of claim 82, wherein said receptor ligand is folic acid.

87. The method of claim 82, wherein said receptor ligand is an RGD peptide.

88. The method of claim 53, wherein said tumor is associated with a neoplastic disease.

89. The method of claim 88, wherein said neoplastic disease is selected from the group consisting of leukemia, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic, (granulocytic) leukemia, chronic lymphocytic leukemia, Polycythemia vera, lymphoma, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s disease, Multiple myeloma, Waldenstrom'"'"'s macroglobulinemia, Heavy chain disease, solid tumors, sarcomas and carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, uterine cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, and neuroblastomaretinoblastoma.