SYSTEM FOR TARGETED DELIVERY OF THERAPEUTIC AGENTS

• US 20100266491A1
• Filed: 09/26/2008
• Published: 10/21/2010
• Est. Priority Date: 03/31/2006
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Original Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Inventors: LANGER, Robert S., ZALE, Stephen E., FAROKHZAD, Omid C., CHENG, Jianjun, TEPLY, Benjamin A.
• Granted Patent: US 8,709,483 B2
• Time in Patent Office: Days
• US Class Current: 424/1.290
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• 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 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 51/0417 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: A61K 51/0495 Pretargeting
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides a drug delivery system for targeted delivery of therapeutic agent-containing particles to tissues, cells, and intracellular compartments. The invention provides targeted particles comprising a particle, one or more targeting moieties, and one or more therapeutic agents to be delivered and pharmaceutical compositions comprising inventive targeted particles. The present invention provides methods of designing, manufacturing, and using inventive targeted particles and pharmaceutical compositions thereof.

Claims

1. A targeted particle, comprising:

a particle;

a targeting moiety; and

a therapeutic agent;

wherein the particle comprises a polymeric matrix, wherein the polymeric matrix comprises a polyester, and wherein the targeting moiety targets prostate cancer cells.

2. The targeted particle of claim 1, wherein the particle is a nanoparticle.

3. The targeted particle of claim 1, wherein the particle is a microparticle.

6. The targeted particle of claim 1, wherein the polyester is selected from the group consisting of PLGA, PLA, PGA, polycaprolactone, and polyanhydrides.

7. The targeted particle of claim 1, wherein the polyester is PLGA.

8. The targeted particle of claim 1, wherein the polymeric matrix comprises two or more polymers.

9. The targeted particle of claim 8, wherein at least one polymer is selected from the group consisting of polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, and combinations thereof.

10. The targeted particle of claim 8, wherein at least one polymer is selected from the group consisting of polyesters, polyanhydrides, polyethers, polyurethanes, polymethacrylates, polyacrylates, and polycyanoacrylates.

11. The targeted particle of claim 8, wherein at least one polymer is polyalkylene glycol.

12. The targeted particle of claim 8, wherein at least one polymer is polyethylene glycol (PEG).

13. The targeted particle of claim 1, wherein the polymeric matrix comprises a copolymer of two or more polymers.

14. The targeted particle of claim 13, wherein the copolymer is a copolymer of PLGA and PEG.

22. The targeted particle of claim 1, wherein the targeted particle comprises a protein, lipid, or carbohydrate.

23. The targeted particle of claim 1, wherein the targeting moiety is a protein.

24. The targeted particle of claim 23, wherein the protein targeting moiety is capable of specifically binding to prostate cancer cells.

25. The targeted particle of claim 23, wherein the protein targeting moiety is selected from the group consisting of antibodies, receptors, cytokines, peptide hormones, avimers, and affibodies.

26. The targeted particle of claim 23, wherein the protein targeting moiety is an antibody that specifically binds to prostate specific membrane antigen (PSMA).

27. The targeted particle of claim 1, wherein the targeting moiety is a small molecule.

28. The targeted particle of claim 27, wherein the small molecule targeting moiety is capable of specifically binding to prostate cancer cells.

29. The targeted particle of claim 27, wherein the small molecule targeting moiety is an antibody that specifically binds to prostate specific membrane antigen (PSMA).

30. The targeted particle of claim 27, wherein the small molecule targeting moiety is selected from the group consisting of folic acid, prostate specific membrane antigen (PSMA) peptidase inhibitors thiol and indole thiol derivatives, hydroxamate derivatives, PBDA-based inhibitors, urea-based inhibitors, androgen receptor targeting agents, and polyamines.

31. The targeted particle of claim 1, wherein the targeting moiety is a nucleic acid.

32. The targeted particle of claim 31, wherein the nucleic acid targeting moiety is an aptamer.

33. The targeted particle of claim 32, wherein the aptamer comprises one or more modified nucleotides and is substantially resistant to endonuclease degradation, exonuclease degradation, or both endonuclease and exonuclease degradation.

34. The targeted particle of claim 32, wherein the aptamer comprises one or more L-enantiomer nucleosides.

35. The targeted particle of claim 32, wherein one or more internal nucleotides at the 3′

-end, 5′

-end, or both 3′

- and 5′

-ends of the aptamer are inverted to yield a 3′

-3′

or a 5′

-5′

nucleotide linkage.

36. The targeted particle of claim 32, wherein the aptamer is capable of specifically binding to prostate cancer cells.

37. The targeted particle of claim 32, wherein the aptamer specifically binds to prostate specific membrane antigen (PSMA).

38. The targeted particle of claim 32, wherein the aptamer comprises the nucleotide sequence of SEQ ID NO.:

1, a derivative thereof, or characteristic portion thereof.

39. The targeted particle of claim 32, wherein the aptamer is homologous to the nucleotide sequence of SEQ ID NO.:

1, a derivative thereof, or characteristic portion thereof.

40. The targeted particle of claim 32, wherein the aptamer comprises the nucleotide sequence of SEQ ID NO.:

2, a derivative thereof, or characteristic portion thereof.

41. The targeted particle of claim 32, wherein the aptamer is homologous to the nucleotide sequence of SEQ ID NO.:

2, a derivative thereof, or characteristic portion thereof.

42. The targeted particle of claim 32, wherein the aptamer comprises the nucleotide sequence of SEQ ID NO.:

3, a derivative thereof, or characteristic portion thereof.

43. The targeted particle of claim 32, wherein the aptamer is homologous to the nucleotide sequence of SEQ ID NO.:

3, a derivative thereof, or characteristic portion thereof.

44. The targeted particle of claim 1, wherein the specific binding of the targeting moiety to a target results in delivery of the therapeutic agent to prostate cancer cells.

45. The targeted particle of claim 44, wherein the target is selected from the group consisting of proteins, nucleic acids, carbohydrates, lipids, and combinations thereof.

46. The targeted particle of claim 44, wherein the target comprises a protein.

47. The targeted particle of claim 45, wherein the target is selected from the group consisting of cell surface receptors, integrins, transmembrane proteins, ion channels, membrane transport proteins, intracellular proteins, soluble proteins, small molecules, tumor markers, characteristic portions thereof, and combinations thereof.

48. The targeted particle of claim 44, wherein the target is a tumor marker.

49. The targeted particle of claim 44, wherein the target is a prostate cancer specific marker.

50. The targeted particle of claim 48, wherein the target is selected from the group consisting of prostate specific antigen, human glandular kallikrein 2, prostatic acid phosphatase, prostate-specific membrane antigen (PSMA), androgen receptor, insulin-like growth factor, insulin-like growth factor binding protein, transmembrane protein 24P4C12, prostate stem cell antigen, calveolin, PHOR-1, C-type lectin transmembrane antigen, protein encoded by 103P2D6, prostatic specific reductase polypeptide, and IL-11 receptor-α

.

51. The targeted particle of claim 48, wherein the target is PSMA.

52. The targeted particle of claim 44, wherein the target is an endothelial cancer specific marker.

53. The targeted particle of claim 44, wherein the target comprises a nucleic acid.

54. The targeted particle of claim 44, wherein the target is a carbohydrate selected from the group consisting of glycoproteins, saccharides, and glycocalyx.

57. The targeted particle of claim 1, wherein the therapeutic agent is selected from the group consisting of small molecules, proteins, nucleic acids, carbohydrates, lipids, and combinations thereof.

58. The targeted particle of claim 1, wherein the therapeutic agent is an anti-cancer agent.

59. The targeted particle of claim 1, wherein the therapeutic agent is selected from the group consisting of antibodies, recombinant antibodies, humanized antibodies, characteristic portions thereof, and combinations thereof.

60. The targeted particle of claim 1, wherein the therapeutic agent is an enzyme.

61. The targeted particle of claim 1, wherein the therapeutic agent is a small interfering RNA, a small hairpin RNA, or a microRNA.

62. The targeted particle of claim 1, wherein the therapeutic agent is a diagnostic agent.

66. The targeted particle of claim 1, wherein the therapeutic agent is a prophylactic agent.

68. The targeted particle of claim 1, wherein the therapeutic agent is a nutraceutical agent.

71. The targeted particle of claim 1, wherein the targeting moiety is non-covalently associated with the particle.

73. The targeted particle of claim 1, wherein the targeting moiety is associated with the particle via at least one covalent linkage.

83. A method of administering a targeted particle to a subject, comprising:

providing a subject, wherein the subject comprises at least one cell;

providing the targeted particle of claim 1; and

administering the targeted particle to the subject.

84. The method of claim 83, wherein the targeted particle further comprises a pharmaceutically acceptable excipient.

91. The method of claim 83, wherein the targeted particle is administered to the subject by an oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical, transdermal, muco sal, nasal, buccal, enteral, or sublingual route.

95. The method of claim 83, wherein the targeted particle is administered directly to the prostate.

96. The method of claim 83, wherein the targeted particle is administered directly to prostate cancer cells.

97. The method of claim 96, wherein the targeted particle is administered directly to prostate cancer cells by topical administration.

98. The method of claim 96, wherein the targeted particle is administered directly to prostate cancer cells by injection into tissue comprising the prostate cancer cells.

99. The method of claim 96, wherein the targeted particle is administered to the subject by implantation of targeted particles at or near prostate cancer cells by stereotactic surgery.

100. The method of claim 96, wherein the targeted particle is administered to the subject by implantation of targeted particles at or near prostate cancer cells during surgical removal of a tumor.

108. The targeted particle of claim 27, wherein the small molecule targeting moiety is selected from the group consisting of a urea-based inhibitor.

4-5. -5. (canceled)

15-21. -21. (canceled)

55-56. -56. (canceled)

63-65. -65. (canceled)

67. (canceled)

69. (canceled)

70. (canceled)

72. (canceled)

74-82. -82. (canceled)

85-90. -90. (canceled)

92-94. -94. (canceled)

101. A method of preparing a targeted particle comprising:

providing a therapeutic agent;

providing a polymer;

providing a targeting moiety;

mixing the polymer with the therapeutic agent to prepare particles; and

associating the particles with the targeting moiety;

wherein the polymer comprises a polyester, and wherein the targeting moiety targets prostate cancer cells.

102-105. -105. (canceled)

106. A targeted particle, comprising:

a particle;

a targeting moiety; and

a therapeutic agent;

wherein the particle comprises a polymeric matrix, wherein the polymeric matrix comprises a polyester, wherein the targeting moiety targets prostate cancer cells, and wherein the targeting moiety is a urea-based inhibitor.

107. The targeted particle of claim 106, wherein the urea-based inhibitor is ZJ 43, ZJ 11, ZJ 17, or ZJ 38.