Claims
- 1. A method of synthesizing a dendritic poly(amino acid) comprising:
a) combining blocked NCA monomers of an amino acid and a dendritic initiator in a solvent to form a reaction mixture; and d) incubating the reaction mixture for about 30 minutes to about 48 hours, wherein a blocked dendritic poly(amino acid) is obtained.
- 2. The method of claim 1, wherein the NCA monomers are selected from the group consisting of glutamic acid, aspartic acid, lysine, and any combination thereof.
- 3. The method of claim 1, wherein the dendritic initiator is selected from the group consisting of branched polymers, oligomers, dendrimers, and any combination thereof.
- 4. The method of claim 1, wherein the dendritic initiator is PEI.
- 5. The method of claim 1, wherein the dendritic initiator is PAMAM.
- 6. The method of claim 1, wherein the dendritic initiator is oligo(lysine).
- 7. The method of claim 1, further comprising conducting the incubation at a temperature range between 4° C. to 100° C.
- 8. The method of claim 1, further comprising deblocking side-chain protecting groups of the blocked dendritic poly(amino acid) to produce deblocked dendritic poly(amino acid).
- 9. The method of claim 8, wherein deblocking comprises bubbling HBr through the reaction mixture.
- 10. The method of claim 9, further comprising bubbling HBr though the reaction mixture for at least 30 minutes.
- 11. The method of claim 8, further comprising extracting the deblocked dendritic poly(amino acid) in a solvent.
- 12. The method of claim 1, wherein the dendritic poly(amino acid) comprises side chains of water-soluble functional groups.
- 13. The method of claim 12, whrein the water-soluble functional groups are selected from the group consisting of carboxyl, amino, and hydroxyl groups and any combination thereof.
- 14. A dendritic poly(amino acid) comprising:
a) a branched polymer central initiator core containing an amine group for attachment of a poly(amino acid) chain, b) a poly(amino acid) chain covalently attached to the central initiator core.
- 15. The dendritic poly(amino acid) of claim 14, wherein each poly(amino acid) chain comprises:
a) a linear structural unit; b) a terminal functional group at the terminus of the linear structural unit; c) a side chain structural unit; and d) a side-chain functional group at the terminus of the side chain structural unit.
- 16. The dendritic poly(amino acid) of claim 14, wherein the central initiator core comprises between 2 and 5000 branches.
- 17. The dendritic poly(amino acid) of claim 14, wherein the branched polymer is PEI.
- 18. The dendritic poly(amino acid) of claim 17, wherein the PEI has a molecular weight of between 500 and 10,000.
- 19. The dendritic poly(amino acid) of claim 17, wherein the PEI further comprises between 2 to 250 amines suitable for initiating polymerization reactions.
- 20. The dendritic poly(amino acid) of claim 14, wherein the branched polymer is PAMAM.
- 21. The dendritic poly(amino acid) of claim 20, further comprising PAMAM having a molecular weight of between 359 and 250,000.
- 22. The dendritic poly(amino acid) of claim 20, wherein the PAMAM comprises between 3 and 1024 surface primary amino groups.
- 23. The dendritic poly(amino acid) of claim 14, wherein the central initiator core comprises a poly(lysine).
- 24. The dendritic poly(amino acid) of claim 23, wherein the branched poly(lysine) comprises between 2 and 128 primary amines suitable for initiating polymerization reactions.
- 25. The dendritic poly(amino acid) of claim 14, wherein the dendritic poly(amino acid) is water-soluble.
- 26. The dendritic poly(amino acid) of claim 15, wherein the terminal functional group is selected from the group consisting of an amine group, a carboxyl group, a sulfhydryl group, a vinylsulfone group, a maleimide group, an isothiocyanatobenzyl group, and any combination thereof.
- 27. The dendritic poly(amino acid) of claim 15, wherein the side-chain functional group is selected from the group consisting of an amine group, a carboxylic acid group, a hydroxyl group, a sulfhydryl group, and any combination thereof.
- 28. The dendritic poly(amino acid) of claim 14, wherein the poly(amino acid) chain comprises a repeating unit selected from the group consisting of L- and/or D-glutamic acid (Glu), L- and/or D-aspartic acid (Asp), lysine (Lys), cysteine (Cys), arginine (Arg), histidine (His), and any combination thereof.
- 29. The dendritic poly(amino acid) of claim 14, wherein the poly(amino acid) chain comprises a repeating unit selected from the group consisting of Ser, Tyr, Thr and any combination thereof.
- 30. The dendritic poly(amino acid) of claim 14, wherein the poly(amino acid) chain comprises a repeating unit selected from the group consisting of Gly, Ala, Val, Leu, Ile, Thr, Trp, Phe, Tyr, Met, and any combination thereof.
- 31. The dendritic poly(amino acid) of claim 15, further comprising a targeting ligand operatively attached to the poly(amino acid) chain.
- 32. The dendritic poly(amino acid) of claim 31, wherein the targeting ligand is operatively attached to the terminal functional group.
- 33. The dendritic poly(amino acid) of claim 31, wherein the targeting ligand comprises a protein, polypeptide, or peptide.
- 34. The dendritic poly(amino acid) of claim 33, wherein the protein, polypeptide, or peptide is selected from the group consisting of annexin V, VEGF, interferon-α, tumor necrosis factor, transferin, RGD-containing peptides, EGF, somatostatin, octreotide, and combinations or functional regions thereof.
- 35. The dendritic poly(amino acid) of claim 31, wherein the targeting ligand comprises an antibody.
- 36. The dendritic poly(amino acid) of claim 35, wherein the antibody comprises a single-chain antibody.
- 37. The dendritic poly(amino acid) of claim 35, wherein the antibody comprises a monoclonal antibody.
- 38. The dendritic poly(amino acid) of claim 37, wherein the monoclonal antibody is selected from the group consisting of Herceptin, anti-EGF receptor antibody, anti-integrin antibody, anti-VEGF receptor, anti-CD13 antibody, and any combination thereof.
- 39. The dendritic poly(amino acid) of claim 31, wherein the targeting ligand comprises an antibody fragment.
- 40. The dendritic poly(amino acid) of claim 15, further comprising a therapeutic agent operatively attached to the poly(amino acid) chain.
- 41. The dendritic poly(amino acid) of claim 40, further comprising the therapeutic agent operatively attached to the side-chain functional group.
- 42. The dendritic poly(amino acid) of claim 40, wherein the therapeutic agent comprises a nucleic acid.
- 43. The dendritic poly(amino acid) of claim 40, wherein the therapeutic agent selected from the group consisting of chemotherapeutics, antibiotics, antiviral agent, antiinflammatories, radiosensitizers, and any combination thereof.
- 44. The dendritic poly(amino acid) of claim 40, wherein the therapeutic agent comprises paclitaxel or docetaxel.
- 45. The dendritic poly(amino acid) of claim 40, wherein the therapeutic agent comprises camptothecins.
- 46. The dendritic poly(amino acid) of claim 40, wherein the therapeutic agent is selected from the group consisting of: epothilones, geldanamycin, etopside, doxorubicin, daunomycin, cisplatin, carboplatin, methotrexate, cyclosporin, emodin, and amphotericin B.
- 47. The dendritic poly(amino acid) of claim 15, further comprising the a diagnostic agent operatively attached to the poly(amino acid) chain.
- 48. The dendritic poly(amino acid) of claim 47, further comprising the diagnostic agent operatively attached to the side-chain functional group.
- 49. The dendritic poly(amino acid) of claim 47, further comprising the diagnostic agent weighing less than 1000 Da.
- 50. The dendritic poly(amino acid) of claim 47, wherein the diagnostic agent comprises an organic compound.
- 51. The dendritic poly(amino acid) of claim 47, wherein the diagnostic agent comprises a radiopaque compound.
- 52. The dendritic poly(amino acid) of claim 51, further comprising the radiopaque compound operable to function as a CT or MRI contrast agent.
- 53. The dendritic poly(amino acid) of claim 51, wherein the radiopaque compound is selected from the group consisting of Iodine, paramagnetic ions, and superparamagnetic metal ions.
- 54. The dendritic poly(amino acid) of claim 53, wherein the paramagnetic ion is selected from the group consisting of Gd, Mn, Dy, Cr, Fe, and any combination thereof.
- 55. The dendritic poly(amino acid) of claim 47, wherein the diagnostic agent comprises a paramagnetic or superparamagnetic ion chelate.
- 56. The dendritic poly(amino acid) of claim 47, wherein the diagnostic agent comprises a near-infrared fluorescent probe.
- 57. The dendritic poly(amino acid) of claim 56, wherein the infrared fluorescent probe comprises a derivate of indocyanine green.
- 58. The dendritic poly(amino acid) of claim 47, wherein the diagnostic agent comprises a radionuclide.
- 59. The dendritic poly(amino acid) of claim 58, further comprising the radionuclide selected from the group consisting of 99 mTc, 111In, 97Ru, 67Cu, 64Cu 67Ga, 68Ga, 72As, 89Zr, 90Y, 201Tl, and any combination thereof.
- 60. A method of preparing a dendrictic poly(amino acid) therapeutic agent comprising:
a) providing a dendritic poly(amino acid) including:
a branched polymeric central initiator core containing an amine group for the attachment of a poly(amino acid) chain, a poly(amino acid) chain including a terminal functional group and a side-chain functional group; b) attaching a targeting ligand to the terminal functional group; and c) attaching a therapeutic agent to the side-chain functional group.
- 61. The method of claim 60 further comprising increasing the water-solubility of the therapeutic agent by attachment to the dendritic poly(amino acid).
- 62. The method of claim 60 further comprising altering the pharmokinetics of the therapeutic agent by attachment to the dendritic poly(amino acid).
- 63. The method of claim 60 further comprising enhancing the therapeutic effect of the therapeutic agent by attachment to the dendritic poly(amino acid).
- 64. A method of preparing a dendritic poly(amino acid) diagnostic agent comprising:
a) providing a dendritic poly(amino acid) including:
a branched polymeric central initiator core containing an amine group for the attachment of a poly(amino acid) chain, a poly(amino acid) chain including a terminal functional group and a side-chain functional group; b) attaching a targeting ligand to the terminal functional group; and c) attaching a diagnostic agent to the side-chain functional group.
- 65. The method of claim 64 further comprising increasing the water-solubility of the diagnostic agent by attachment to the dendritic poly(amino acid).
- 66. The method of claim 64, further comprising altering the pharmokinetics of the diagnostic agent by attachment to the dendritic poly(amino acid).
- 67. A method of delivering a therapeutic agent to a target location in a mammal comprising:
a) providing a dendritic poly(amino acid) including:
a branched polymeric central initiator core containing an amine group for the attachment of a poly(amino acid) chain; and a poly(amino acid) chain including a terminal functional group to which a targeting ligand is attached and a side-chain functional group to which a therapeutic agent is attached; and b) administering the dendritic poly(amino acid) to the mammal.
- 68. The method of claim 67, wherein the target location is selected from the group consisting of an organelle, a cell, a tissue, and an organ in need of therapy.
- 69. The method of claim 67, wherein the therapeutic agent comprises a nucleic acid.
- 70. The method of claim 67, wherein the therapeutic agent is selected from the group consisting of chemotherapeutics, antibiotics, antiviral agent, antiinflammatories, radiosensitizers, and any combination thereof.
- 71. The method of claim 67, wherein the therapeutic agent is administered using a method selected from the group consisting of intravenously, intraperitoneally, intra-arterially, intratumorally, intramuscularlly, intrathacheally, subcutaneouly, and any combination thereof.
- 72. A method of delivering a diagnostic agent to a target location in a mammal comprising:
a) providing a dendritic poly(amino acid) including:
a branched polymeric central initiator core containing an amine group for the attachment of a poly(amino acid) chain; and a poly(amino acid) chain including a terminal functional group to which a targeting ligand is attached and a side-chain functional group to which a diagnostic agent is attached; and b) administering the dendritic poly(amino acid) to the mammal.
- 73. The method of claim 72, wherein the target location is selected from the group consisting of an organelle, acell, atissue, and an organ.
- 74. The method of claim 72, wherein the diagnostic agent is administered using a method selected from the group consisting of intravenously, intraperitoneally, intra-arterially, intratumorally, intramuscularlly, intratracheally, subcutaneouly, and any combination thereof.
- 75. The method of claim 72, wherein the diagnostic agent comprises an agent selected from the group consisting of radiopaque compounds suitable as CT-contrast agents, paramagnetic and superparamagnetic ions, paramagnetic and superparamagnetic ion chelates, infrared fluorescent probes, radionuclides, and any combination thereof.
PRIORITY CLAIM
[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Serial No. 60/342,807, filed Dec. 21, 2001, entitled “Dendritic Poly(Amino Acid) Carriers”.
STATEMENT OF GOVERNMENT INTEREST
[0002] The present invention was developed under a grant from the National Institutes of Health/National Cancer Institute grant No. CA74819. The U.S. Government may have certain rights to the invention.
Provisional Applications (1)
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Number |
Date |
Country |
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60342807 |
Dec 2001 |
US |