Targeted therapeutic delivery of vitamin D compounds

• US 20030129194A1
• Filed: 09/20/2002
• Published: 07/10/2003
• Est. Priority Date: 02/13/1997
• Status: Abandoned Application

• Current Assignee: Bone Care International LLC
• Original Assignee: Bone Care International LLC
• Inventors: Bishop, Charles W., Mazess, Richard B.
• Application Number:
  US10/251,905
• Publication Number:
  US 20030129194A1
• Time in Patent Office: Days
• US Class Current: 424/178.1
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 47/6898 using avidin- or biotin-conjugated antibodies
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 16/30 from tumour cells

Abstract

The present invention is directed to a conjugate which includes at least one vitamin D moiety thereof and at least one targeting molecule moiety to pharmaceutical compositions of the conjugate, and to methods for using the conjugate for target-specific delivery of vitamin D or analogs thereof to tissues in need thereof. When a particularly preferred form is administered to a patient, the targeting molecule component of the conjugate of this invention seeks out and binds to a tissue of interest, such as bone or tumor tissue, where the vitamin D has a therapeutic effect.

Claims

1. A method of inhibiting hyperproliferation of malignant or neoplastic cells, comprising treating the cells with an antiproliferative amount of a vitamin D conjugate, the conjugate comprising a vitamin D moiety and a tumor-seeking moiety.

2. A method as set forth in claim 1, where the cells comprise a vitamin D receptor.

3. A method as set forth in claim 2, wherein the cells are cancers of the breast, colon, lung, neck and head, pancreas, endometrium, bladder, cervix, testes, prostate, skin, ovaries, liver, skin carcinoma, small cell and non-small cell cancer of the lung, squamous cell carcinoma, myeloid and lymphocytic leukemias, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.

4. A method as set forth in claim 3, wherein an amount of the conjugate is administered to a human patient in need thereof which amount is effective to inhibit growth of the cells.

5. A method as set forth in claim 1, wherein the vitamin D moiety includes a moiety of at least one of 1α

-dihydroxyvitamin D₂, 1α

,2-dihydroxyvitamin D₄, 1α

,24-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₃, 1α

hydroxyvitamin D₃, 1α

,25-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₄, 1α

,24,25-dihydroxyvitamin D₂, seocalcitol, calcipotriol, maxacalcitol, falecalcitriol, and paricalcitol.

6. A method as set forth in claim 1, wherein the tumor-seeking moiety includes at least one of antibodies, oxidized glycosylated proteins, polylysine, human serum albumin, dextrans, peptides and proteins having affinity for cellular receptors, polyanionic compounds and polymers, polysulphated compounds and polymers, and peptide analogs.

7. A method as set forth in claim 6, wherein the antibodies includes at least one of antibodies for vascular permeability factor and monoclonal antibodies.

8. A method as set forth in claim 6, wherein the cellular receptors includes at least one of gastrin releasing peptide receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, tumor necrosis factor receptor, fibroblast growth factor receptor, insulin-like growth factor receptor, transfertin receptor, laminin receptor, cytokine receptors, fibronectin receptor, interleukin receptor, interferon receptors, bombesen/gastrin-releasing peptide receptor, and somatostatin receptor.

9. A method as set forth in claim 6, wherein polyanionic compounds and polymers include at least one of sumarin, and analogues and derivatives of sumarin.

10. A method as set forth in claim 6, wherein the polysulphated compounds and polymers include at least one of heparin, heparan sulfate, chrondroitin sulfate, keratan sulfate, dermatan sulfate, sulfated chitin, sulfated chitosan, sulfated alginic acid, pentosan polysulfate, sulfated cyclodextrins, polystyrene sulfonate, sulfated polyvinyl alcohol, polyvinyl sulfate, and polyethylene sulfonate.

11. A method as set forth in claim 6, wherein the peptide analogs include at least one of analogs of LH-RH, dombesin, and somatostatin.

19. A method as set forth in claim 1 wherein the cells are hepatic tumors and the target molecule includes a medium-chain triglyceride.

12. A method of treating a human to alleviate the pathological effects of breast cancer, colon cancer, testicular cancer, pancreatic cancer, endometrial cancer, prostate cancer, skin carcinoma, small cell and non-small cell cancer of the lung, squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocytic leukemias, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma, retinoblastoma, soft tissue sarcoma, bone sarcoma, or psoriasis comprising administering to the human a therapeutic amount of a vitamin D conjugate, the conjugate comprising a vitamin D moiety and a target molecule moiety.

13. A method as set forth in claim 12, wherein the vitamin D conjugate further comprises a moiety which is a therapeutic agent other than vitamin D.

14. A method as set forth in claim 13, wherein the therapeutic agent is a cytotoxic agent.

15. A method as set forth in claim 14, wherein the cytotoxic agent includes at least one of an antimetabolite, antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, an antibiotic, a hormone or a biological response modifier.

16. A method as set forth in claim 15, wherein the antimicrotubule agent includes at least one of vincristine, vinblastine and a taxane.

17. A method as set forth in claim 15, wherein the taxane includes at least one of paclitaxel and docetaxel.

18. A method as set forth in claim 12, wherein a therapeutic amount of the vitamin D conjugate provides an amount of the cytotoxic agent which is lower than the antiproliferative effective amount of the cytotoxic agent when administered alone.

20. A method as set forth in claim 12, wherein the pathological effect is due to hepatic tumors and the target molecule includes a medium-chain triglyceride.

21. A compound of the formula

D-[(J)_z-L-AP]

wherein D is a vitamin D moiety;

J is an acid cleavable linker which is covalently bonded to D;

z is 0, 1 or 2;

L is a linking moiety; and

AP is a moiety which is a phosphonic acid ligand.

22. A compound as set forth in claim 21 wherein AP is selected from the group consisting of a 1-hydroxyethylidene-1-bisphosphonic ligand, a dichloromethylene bisphosphonic acid ligand, a 3-amino-1-hydroxypropylidene-1-bisphosphonic acid ligand and a polyaminomethylenephosphonic acid ligand.

23. A compound as set forth in claim 21, wherein the vitamin D moiety includes a moiety of at least one of 1α

-dihydroxyvitamin D₂, 1α

,2-dihydroxyvitamin D₄, 1α

,24-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₃, la hydroxyvitamin D₃, 1α

,25-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₄, 1α

,24,25-dihydroxyvitamin D₂, seocalcitol, calcipotriol, maxacalcitol, falecalcitriol, and paricalcitol.

24. A method of site-specific delivery of a vitamin D moiety to bone in a patient, the method comprising administering to the patient a therapeutically effective dose of the compound of claim 21.

25. The method of claim 24, wherein AP is selected from the group consisting of a 1-hydroxyethylidene-1-bisphosphonic ligand, a dichloromethylene bisphosphonic acid ligand, a 3-amino-1-hydroxypropylidene-1-bisphosphonic acid ligand and a polyaminomethylenephosphonic acid ligand.

26. A pharmaceutical composition comprising the compound of claim 21 and a pharmaceutically acceptable vehicle.

32. The method of claim 21, wherein the bone-seeking molecule includes at least one of tetracycline, DHEA, calcitonin, a bisphosphonate, a chelator, a phosphate, polyaspartic acid, polyglutamic acid, an aminophosphosugar, an estrogen, a peptide associated with mineral phase of bone such as osteonectin, bone sialoprotein and osteopontin, and a protein with bone mineral binding domains.

27. A method of treating bone diseases in a human subject, comprising administering to the subject an effective amount of a vitamin D conjugate, the conjugate comprising a vitamin D moiety and a bone-seeking molecule moiety.

28. A method as set forth in claim 27, wherein the bone-seeking molecule is a peptide having an affinity for bone.

29. A method as set forth in claim 28, wherein the peptide is a small acidic peptide.

30. A method as set forth in claim 29, wherein the peptide is (Asp)₆ or (Glu)₆.

31. A method as set forth in claim 28, wherein the peptide is associated with osteonection, bone sialoprotein or osteopontin.

34. A targeted delivery system comprising a vitamin D molecule bound to a targeting moiety.

33. A method as set forth in claim 34, wherein the bisphosphonate includes at least one of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, zoledronate and combinations thereof.

35. A targeted delivery system as set forth in claim 34, wherein the vitamin D molecule includes at least one of 1α

-dihydroxyvitamin D₂, 1α

,2-dihydroxyvitamin D₄,1α

,24-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₃, 1α

hydroxyvitamin D₃, 1α

,25-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₄, 1α

,24,25-dihydroxyvitamin D₂, seocalcitol, calcipotriol, maxacalcitol, falecalcitriol, and paricalcitol.

36. A targeted delivery system as set forth in claim 34, wherein the targeting moiety includes DHEA.

37. A targeted delivery system as set forth in claim 34, wherein the targeting moiety includes a peptide.

38. A system as set forth in claim 37, wherein the peptide has an affinity to bone.

43. A system as set forth in claim 37, wherein the peptide is a peptide associated with osteonectin, bone sialoprotein or osteopontin.

44. A system as set forth in claim 34, further comprising at least one therapeutic agent other than a vitamin D molecule.

45. A system as set forth in claim 44, wherein the therapeutic agent includes at least one of conjugated estrogens or their equivalents, antiestrogens, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin, boron, dehydroepiandrosterone, transforming bone growth factor beta, activin, and bone morphogenic protein.

46. A system as set forth in claim 44, wherein the therapeutic agent includes at least one of estromustene phosphate, prednimustine, cisplatin, S-fluorouracil, melphalan, hydroxyurea, mitomycin, idarubicin, methotrexate, adriamycin and daunomycin.

39. A system as set forth in claim 39, wherein the affinity is for hydroxyapatite (HA) formed in the osteoblasts of the matrix of bone.

40. A system as set forth in claim 39, wherein the peptide is a small acidic peptide.

41. A system as set forth in claim 40, wherein the small acidic peptide is (Asp)₆.

42. A system as set forth in claim 40, wherein the small acidic peptide is (Glu)₆.

47. A pharmaceutical composition comprising:

a conjugate which includes at least one vitamin D moiety associated with at least one peptide having an affinity for bone, and a pharmaceutically acceptable carrier.

48. The pharmaceutical composition of claim 47, where in affinity of the peptide is for the matrix of bone wherein hydroxyapatite (HA) is formed in the osteoblasts.

49. The pharmaceutical composition of claim 47, wherein the peptide includes a small acidic peptide.

50. The pharmaceutical composition of claim 49, wherein the small acidic peptide includes (Asp)₆.

51. The pharmaceutical composition of claim 49, wherein the small acidic peptide includes (GIu)₆.

52. The pharmaceutical composition of claim 47, wherein the peptide includes a peptide associated with osteonectin, bone sialoprotein or osteopontin.

53. The pharmaceutical composition of claim 47, further comprising a differentially degradable coating encapsulating the conjugate for time release delivery of the conjugate.

54. A kit for the targeted delivery of an active vitamin D molecule, comprising:

at least one dosage unit containing a composition comprising a conjugate of a targeting moiety and a vitamin D moiety.

55. The kit of claim 54, wherein the targeting moiety includes a bone seeking agent.

56. A method of treating tumors, comprising:

administering to a patient a composition comprising a conjugate of an antibody, or a fragment or a derivative thereof, and a vitamin D molecule in a therapeutically effective dosage.

57. A method of targeted delivery of a therapeutic agent to cancer tissue comprising:

conjugating an active vitamin D compound to an antibody which binds to a cell-surface antigen of cells of the cancer tissue and administering the conjugated antibody to a patient.