Method to enhance tissue accumulation of radiolabeled compounds

• US 6,180,082 B1
• Filed: 11/23/1998
• Issued: 01/30/2001
• Est. Priority Date: 11/24/1997
• Status: Expired due to Fees

• Current Assignee: Board of Supervisors of Louisiana State University Agricultural & Mechanical College (Louisiana State University System)
• Original Assignee: Board of Supervisors of Louisiana State University Agricultural & Mechanical College (Louisiana State University System)
• Inventors: Woltering, Eugene A., Espenan, Gregory D.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/198,562
• Time in Patent Office: 799 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.69, 424/9.1, 530/300, 530/311, 530/317, 530/324-330
• US Class Current: 424/1.69
• CPC Class Codes: A61K 51/08 Peptides, e.g. proteins , carriers being peptides, polyamino acids, proteins
• CPC Class Codes: A61K 51/083 the peptide being octreotide or a somatostatin-receptor-binding peptide

Abstract

Administration of a radioisotopic compound by infusion over a period of time greater than two hours, preferably greater than twelve hours, greatly increases the maximum radioactivity that accumulates in the target cell. The efficacy of the administration of the radiolabeled compound can be increased about five times higher than prior bolus injection or short infusion methods. This method enhances the tumor to background ratio by increasing the actual radioligand accumulated inside the target cells. This technique works for any radiolabeled compound whose cellular uptake is limited by a cellular process of either binding to a cellular receptor or to a transport protein. Once the radiolabeled compound is bound and internalized, the ability of an unlabeled compound to compete with the radioligand is markedly decreased. The primary factor governing residence time after internalization is the physical half-life of the radioisotope, not biologic half-life.

Claims

1. A method for selectively accumulating a receptor-dependent radiolabeled compound inside target cells in a patient, wherein the target cells are selected from the group consisting of tumor cells and angiogenic cells, wherein the target cells express receptors for the radiolabeled compound, comprising administering a dose of the radiolabeled compound to the patient by infusion during a period greater than two hours, wherein the resulting residence time of the radiolabeled compound in the target cells is at least one and one-half (1.5) times the residence time of the radiolabeled compound in the target cells that would result from a bolus administration of the same total dose of the same radiolabeled compound to the patient.

2. The method of claim 1, wherein the rate of infusion is approximately equal to the rate of cellular uptake and translocation to the nucleus of the radiolabeled compound by the tumor cells.

3. The method of claim 1, wherein the period of infusion is between about 4 hours and about 30 days.

4. The method of claim 1, wherein the period of infusion is between about 24 hours and about 5 days.

5. The method of claim 1, wherein said target cells are tumor cells.

6. The method of claim 1, wherein said target cells are angiogenic cells.

7. The method of claim 1, wherein said radiolabeled compound comprises a receptor-dependent peptide bound to a radioisotope.

8. The method of claim 7, wherein said receptor-dependent peptide is selected from the group consisting of nerve growth factor, fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, cholecystokinin, vasoactive intestinal peptide, gastrin-releasing peptide, leukemia inhibitory factor, somatostatin, oxytocin, bombesin, calcitonin, arginine vasopressin, angiotensin II, atrial natriuretic peptide, insulin, glucagon, prolactin, growth hormone, gonadotropin, thyrotropin-releasing hormone, growth hormone-releasing hormone, gonadotropin-releasing hormone, corticotropin-releasing hormone, interleukins, interferons, transferrin, substance P, neuromedin, neurotensin, neuropeptide Y, and opioids.

9. The method of claim 7, wherein said receptor-dependent peptide is somatostatin.

10. The method of claim 7, wherein said receptor-dependent peptide is vascular endothelial growth factor and said target cells are angiogenic cells.

11. The method of claim 7, wherein said receptor-dependent peptide is platelet-derived growth factor and said target cells are angiogenic cells.

12. The method of claim 7, wherein said receptor-dependent peptide is a somatostatin analog.

13. The method of claim 12, wherein said somatostatin analog is selected from the group consisting of octreotide, pentetreotide, vapreotide, lanreotide, WOC-3b, WOC-4a, and JIC-2D.

14. The method of claim 12, wherein said somatostatin analog is pentetreotide.

15. The method of claim 12, wherein said somatostatin analog is WOC-4a.

16. The method of claim 12, wherein said somatostatin analog is WOC-3b.

17. The method of claim 12, wherein said somatostatin analog is JIC-2D.

18. The method of claim 7, wherein said radioisotope has a half-life between about 1 hour and about 60 days.

19. The method of claim 7, wherein said radioisotope has a half-life between about 2 hours and about 60 days.

20. The method of claim 7, wherein said radioisotope has a half-life between about 12 hours and about 60 days.

21. The method of claim 7, wherein said radioisotope is selected from the group consisting of ⁶⁷Ga, ¹¹¹In, ^99mTc, ⁹⁰Y, ⁸⁶Y, ¹⁶⁹Yb, ¹⁸⁸Re, ¹²⁵I, ¹²³I, ¹²⁴I, ¹²⁹I, ¹³¹I, and ⁷⁷Br.

22. The method of claim 7, wherein said radioisotope is ¹¹¹In.

23. The method of claim 7, wherein said radioisotope is ¹²⁵I.

24. The method of claim 7, wherein said radioisotope is ¹³¹I.

25. The method of claim 1, wherein said radiolabeled compound is selected from the group consisting of ¹¹¹In-pentetreotide (¹¹¹In-DTPA-D-Phe¹-octreotide), (¹¹¹In-DOTA⁰-D-Phe¹-Tyr³)-octreotide, (⁹⁰Y-DOTA⁰-D-Phe¹-Tyr³)-octreotide, (⁸⁶Y-DOTA⁰-D-Phe¹-Tyr³)-octreotide, ¹¹¹In-DTPA-D-Phe¹-RC-160, ^99mTc-RC-160, ^99mTc-CPTA-RC-160, ¹²³I-RC-160, ¹²⁵-RC-160, ¹³¹I-RC-160, ^99mTc-octreotide, ¹⁸⁸Re-RC-160, ¹²³I-tyr³-octreotide, ¹²⁵I-tyr³-octreotide, ¹³¹I-tyr³-octreotide, ¹²⁵I-lanreotide, ¹²³I-lanreotide, ¹³¹I-lanreotide, ⁹⁰Y-DOTA-lanreotide, ⁸⁶Y-DOTA-lanreotide, ¹¹¹In-DPTA-lanreotide, ¹¹¹In-DOTA-lanreotide, ¹¹¹In-DPTA-somatostatin, ⁹⁰Y-DOTA-somatostatin, ⁸⁶Y-DOTA-somatostatin, ¹²⁵I-somatostatin, ¹³¹I-WOC-3b, ¹²⁵I-WOC-3b, ¹³¹I-WOC-4a, ¹²⁵I-WOC-4a, ¹²⁵I-JIC-2D, ¹²³I-JIC-2D, and ¹³¹I-JIC-2D.

26. The method of claim 25, wherein said radiolabeled compound is accumulated in cells of tumors selected from the group consisting of endocrine tumors, melanomas, breast carcinomas, Merkel cell tumors, lymphomas, small cell lung carcinomas, gastrointestinal tumors, astrocytomas, gliomas, meningiomas, carcinoid tumors, islet cell tumors, renal cell carcinomas, neuroblastomas, and pheochromocytomas.

27. The method of claim 25, wherein said radiolabeled compound is accumulated in angiogenic cells.

28. The method of claim 1, wherein said radiolabeled compound is ¹¹¹In-pentetreotide.

29. The method of claim 28, wherein said radiolabeled compound is accumulated in tumor cells selected from the group consisting of pituitary tumors, endocrine pancreatic tumors, carcinoids, paragangliomas, pheochromocytomas, medullary thyroid carcinomas, small cell lung carcinomas, neuroblastomas, meningiomas, lymphomas, glucagonomas, breast carcinomas, renal cell carcinomas, gliomas, astrocytomas, and melanomas.

30. The method of claim 28, wherein said radiolabeled compound is accumulated in angiogenic cells.

31. The method of claim 28, wherein said radiolabeled compound is accumulated in neuroblastoma cells.

32. The method of claim 28, wherein said radiolabeled compound is accumulated in small cell-lung carcinoma cells.

33. The method of claim 28, wherein said radiolabeled compound is accumulated in endocrine tumor cells.

34. The method of claim 1, wherein said radiolabeled compound is ¹²⁵I-WOC-4a.

35. The method of claim 34, wherein said radiolabeled compound is accumulated in neuroblastoma cells.

36. The method of claim 34, wherein said radiolabeled compound is accumulated in angiogenic cells.

37. The method of claim 1, wherein said radiolabeled compound is ¹³¹I-WOC-4a.

38. The method of claim 37, wherein said radiolabeled compound is accumulated in neuroblastoma cells.

39. The method of claim 37, wherein said radiolabeled compound is accumulated in angiogenic cells.

40. The method of claim 1, wherein said radiolabeled compound is ¹²⁵I-WOC-3b.

41. The method of claim 40, wherein said radiolabeled compound is accumulated in neuroblastoma cells.

42. The method of claim 40, wherein said radiolabeled compound is accumulated in angiogenic cells.

43. The method of claim 1, wherein said radiolabeled compound is ¹²⁵I-somatostatin.

44. The method of claim 1, wherein said radiolabeled compound is ¹²⁵I-JIC-2D.

45. The method of claim 44, wherein said radiolabeled compound is accumulated in angiogenic cells.

46. The method of claim 5, wherein said radiolabeled compound comprises a receptor-dependent steroid bound to a radioisotope.

47. The method of claim 46, wherein said receptor-dependent steroid is selected from the group comprising estrogen, testosterone, progesterone, glucocorticosteriods, and mineralocorticoids.

48. The method of claim 46, wherein said receptor-dependent steroid is estradiol.

49. The method of claim 46, wherein said radioisotope has a half-life between about 1 hour and about 60 days.

50. The method of claim 46, wherein said radioisotope has a half-life between about 5 hours and about 60 days.

51. The method of claim 46, wherein said radioisotope has a half-life between about 12 hours and about 60 days.

52. The method of claim 46, wherein said radioisotope is selected from the group consisting of ⁶⁷Ga, ¹¹¹In, ^99mTc, ⁹⁰Y, ⁸⁶Y, ¹⁶⁹Yb, ¹⁸⁸Re, ¹²⁵I, ¹²³I, ¹²⁴I, ¹²⁹I, ¹³¹I, and ⁷⁷Br.

53. The method of claim 46, wherein said radioisotope is ¹²⁵I.

54. The method of claim 5, wherein said radiolabeled compound is ¹²⁵I-17-β

-estradiol.

55. The method of claim 54, wherein said radiolabeled compound is accumulated in breast cancer cells.

56. The method of claim 1, further comprising the step of imaging radioactivity in the area of said target cells by scintigraphy.

57. The method of claim 1, further comprising the step of repeating the process of claim 1 until there is at least a 50% decrease in a tumor marker as measured by biochemical and radiographical techniques.