Methods and apparatus for image-guided ultrasound delivery of compounds through the blood-brain barrier

• US 5,752,515 A
• Filed: 08/21/1996
• Issued: 05/19/1998
• Est. Priority Date: 08/21/1996
• Status: Expired due to Term

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Jolesz, Ferenc A., Hynynen, Kullervo
• Primary Examiner(s): Lateef, Marvin M.
• Assistant Examiner(s): SHAW, SHAWNA JEANNINE
• Application Number:
  US08/711,289
• Time in Patent Office: 636 Days
• Field of Search: 128/653.1, 128/653.2, 128/653.4, 128/654, 128/660.01, 128/898, 601/2, 601/3, 601/4, 424/9.3, 604/22, 604/890.1, 604/892.1
• US Class Current: 600/458
• CPC Class Codes: A61B 2017/22008 used or promoted
• CPC Class Codes: A61B 2017/22028 arrays, e.g. phased arrays
• CPC Class Codes: A61B 2090/374 NMR or MRI
• CPC Class Codes: A61B 2090/376 using X-rays, e.g. fluoroscopy
• CPC Class Codes: A61B 5/055 involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
• CPC Class Codes: A61B 8/08 Detecting organic movements or changes, e.g. tumours, cysts, swellings A61B8/02 - A61B8/06 take precedence
• CPC Class Codes: A61B 8/0808 for diagnosis of the brain
• CPC Class Codes: A61B 8/481 involving the use of contrast agent, e.g. microbubbles introduced into the bloodstream analysis of echo signal exploiting properties of a contrast enhancer in devices for short-range imaging with acoustic waves G01S7/52039
• CPC Class Codes: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
• CPC Class Codes: A61N 7/00 Ultrasound therapy lithotripsy A61B17/22, A61B17/225; massage using supersonic vibration A61H23/00 ; using ultrasound for introducing media into the body A61M37/0092

Abstract

Image-guide methods and apparatus for ultrasound delivery of compounds through the blood-brain barrier to selected locations in the brain target a selected location in the brain and applying ultrasound to effect in the tissues and/or fluids at that location a change detectable by imaging. At least a portion of the brain in the vicinity of the selected location is imaged, e.g., via magnetic resonance imaging, to confirm the location of that change. A compound, e.g., a neuropharmaceutical, in the patient'"'"'s bloodstream is delivered to the confirmed location by applying ultrasound to effect opening of the blood-brain barrier at that location and, thereby, to induce uptake of the compound there.

Claims

1. A method for delivering a compound from the bloodstream to a selected location in the brain, the method comprising:

A. applying ultrasound to a selected location in the brain to effect at that location a change detectable by imaging,

B. generating a radiologic image of at least a portion in the brain to confirm the location of that change, and

C. applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake at that location a compound from the bloodstream.

2. A method according to claim 1, wherein steps (A) and (C) include the step of delivering the ultrasound through the skull.

3. A method according to claim 2, wherein steps (A) and (C) include the step of delivering the ultrasound using any of (i) a phased array, (ii) a focused ultrasound transducer, and (iii) a combination of an ultrasound source and acoustic lens.

4. A method according to claim 1, wherein steps (A) and (C) include the steps of

exposing dura matter of the brain,

delivering the ultrasound substantially at or beneath the exposed dura matter.

5. A method according to claim 1, wherein step (B) includes the step of generating a radiologic image of at least a portion of the brain in the vicinity of the selected location.

6. A method according to claim 1, comprising admitting the compound into the patient'"'"'s bloodstream at least in a vicinity of the selected location.

7. A method according to claim 1, wherein step (C) includes the step of delivering the ultrasound to the confirmed location in the brain to open the blood-brain barrier by cavitation.

8. A method according to claim 7, wherein step (C) includes the step of delivering the ultrasound to the confirmed location in the brain at a frequency ranging from 20 kHz to 10 MHz, sonication duration ranging from 100 nanoseconds to 30 minutes, with continuous wave or burst mode operation, where the burst mode repetition varies from 0.01 Hz to 1 MHz.

9. A method according to claim 1, wherein step (C) includes the step of delivering the ultrasound to the confined location in the brain to open the blood-brain barrier by heating.

10. A method according to claim 9, wherein step (C) includes the step of delivering the ultrasound to the confirmed location in the brain at a frequency ranging from 250 kHz to 10 MHz, and with sonication duration ranging from 0.10 microseconds to 30 minutes.

11. A method according to claim 1, wherein step (A) includes the step of delivering the ultrasound to the selected location in the brain to induce by cavitation the change detectable by imaging.

12. A method according to claim 11, wherein step (A) includes the step of delivering the ultrasound to the selected location in the brain at a frequency ranging from 20 kHz to 5 MHz, and with sonication duration ranging from 100 nanoseconds to 1 minute.

13. A method according to claim 1, wherein step (A) includes the step of delivering the ultrasound to the selected location in the brain to induce by heating the change detectable by imaging.

14. A method according to claim 13, wherein step (A) includes the step of delivering the ultrasound to the selected location in the brain at a frequency ranging from 200 kHz to 10 MHz, and with sonication duration ranging from 100 milliseconds to 30 minutes.

15. A method according to any of claims 11-14, wherein step (A) includes the steps of

introducing a contrast agent into the patient, at least in a vicinity of the selected location in the brain, and

effecting a change at that location detectable by imaging by applying ultrasound there to open the blood-brain barrier and, thereby, induce uptake of the contrast agent there.

16. A method according to claim 1, wherein step (C) includes the step of introducing into the patient'"'"'s bloodstream a compound including any of a contrast agent, a neuropharmacologic agent, a neuroactive peptides, a protein, an enzyme, a gene therapy agent, a neuroprotective factor, a growth factor, a biogenic amine, a trophic factor to any of brain and spinal transplants, an immunoreactive proteins, a receptor binding protein, a radioactive agent, an antibody, and a cytotoxin.

17. A method for delivering a compound to a selected location in the brain of a patient, the method comprising:

A. introducing a contrast agent into the patient'"'"'s bloodstream, at least in a vicinity of the selected location in the brain,

B. applying ultrasound to the selected location to open the blood-brain barrier and, thereby, induce uptake of the contrast agent there,

C. taking a radiologic image of at least a portion of the brain to confirm the location to which ultrasound was delivered,

D. introducing the compound into the patient'"'"'s bloodstream at least in a vicinity of the confirmed location, and

E. applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake of the compound there.

18. An apparatus for delivering a compound to a selected location in the brain of a patient, the apparatus comprising:

A. an ultrasound source,

B. targeting means, coupled to the ultrasound source, for applying ultrasound to the selected location in the brain to effect at that location a change detectable by imaging,

C. imaging means for generating a radiologic image of at least a portion of the brain to confirm the location of that change, and

D. delivery means, coupled to the ultrasound source, for applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake of the compound there.

19. An apparatus according to claim 18, wherein at least one of the targeting means and the delivery means includes means for delivering the ultrasound through the skull.

20. An apparatus according to claim 19, wherein at least one of the targeting means and the delivery means comprises any of (i) a phased array, (ii) a focused ultrasound transducer, and (iii) a combination of an ultrasound source and acoustic lens.

21. An apparatus according to claim 18, wherein at least one of the targeting means and the delivery means includes means for delivering the ultrasound substantially at or beneath exposed dura matter.

22. An apparatus according to claim 18, wherein the imaging means comprises means for generating a radiologic image of at least a portion of the brain in the vicinity of the selected location.

23. An apparatus according to claim 18, wherein the delivery means includes means for delivering the ultrasound to the confirmed location in the brain to open the blood-brain barrier by cavitation.

24. An apparatus according to claim 23, wherein the delivery means includes means for delivering the ultrasound to the confirmed location in the brain at a frequency ranging from 20 kHz to 10 MHz, sonication duration ranging from 100 nanoseconds to 30 minutes, with continuous wave or burst mode operation, where the burst mode repetition varies from 0.01 Hz to 1 MHz.

25. An apparatus according to claim 18, wherein the delivery means includes means for delivering the ultrasound to the confirmed location in the brain to open the blood-brain barrier by heating.

26. An apparatus according to claim 25, wherein the delivery means includes means for delivering the ultrasound to the confirmed location in the brain at a frequency ranging from 250 kHz to 10 MHz, and with sonication duration ranging from 0.10 microseconds to 30 minutes.

27. An apparatus according to claim 18, wherein the targeting means includes means for delivering the ultrasound to the selected location in the brain to effect radiologic activity by cavitation.

28. An apparatus according to claim 27, wherein the targeting means includes means for delivering the ultrasound to the selected location in the brain at a frequency ranging from 20 kHz to 5 MHz, and with sonication duration ranging from 100 nanoseconds to 1 minute.

29. An apparatus according to claim 18, wherein the targeting means includes means for delivering the ultrasound to the selected location in the brain to induce by heating the change detectable by imaging.

30. An apparatus according to claim 29, wherein the targeting means includes means for delivering the ultrasound to the selected location in the brain at a frequency ranging from 200 kHz to 10 MHz, and with sonication duration ranging from 100 milliseconds to 30 minutes.

31. An apparatus for delivering a compound to a selected location in the brain of a patient, the method comprising,

A. an ultrasound source,

B. targeting means, coupled to the ultrasound source, for applying ultrasound to the selected location to open the blood-brain barrier and, thereby, induce uptake of the contrast agent there,

C. imaging means for taking a radiologic image of at least a portion of the brain to confirm the location to which ultrasound was delivered, and

D. delivery means, coupled to the ultrasound source, for applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake of the compound there.

32. A method for delivering a compound from the bloodstream to a selected location in the brain, the method comprising:

A. applying ultrasound to a selected location in the brain to (i) induce a change at that location detectable by imaging, and (ii) open the blood-brain barrier at that location and, thereby, induce uptake of the compound at that location, and

B. generating a radiologic image of at least a portion in the brain to confirm the location of the change detectable by imaging.

33. A method according to claim 32, wherein step (A) includes the step of delivering the ultrasound through the skull.

34. A method according to claim 33, wherein step (A) includes the step of delivering the ultrasound using any of (i) a phased array, (ii) a focused ultrasound transducer, and (iii) a combination of an ultrasound source and acoustic lens.

35. A method according to claim 32, wherein step (A) includes the steps of

exposing dura matter of the brain,

delivering the ultrasound substantially at or beneath the exposed dura matter.

36. A method according to claim 32, wherein step (B) includes the step of generating a radiologic image of at least a portion of the brain in the vicinity of the selected location.

37. A method according to claim 32, comprising admitting the compound into the patient'"'"'s bloodstream at least in a vicinity of the selected location.

38. A method according to claim 32, wherein step (A) includes the step of delivering the ultrasound to the selected location in the brain to induce at that location a change detectable by imaging and to open the blood-brain barrier by cavitation.

39. A method according to claim 38, wherein step (A) includes the step of delivering the ultrasound to the selected location in the brain at a frequency ranging from 20 kHz to 10 MHz, sonication duration ranging from 100 nanoseconds to 30 minutes, with continuous wave or burst mode operation, where the burst mode repetition varies from 0.01 Hz to 1 MHz.

40. A method according to claim 32, wherein step (A) includes the step of delivering the ultrasound to the selected location in the brain to induce by heating the change detectable by imaging and to open the blood-brain barrier.

41. A method according to claim 40, wherein step (A) includes the step of delivering the ultrasound to the selected location in the brain at a frequency ranging from 250 kHz to 10 MHz, and with sonication duration ranging from 0.10 microseconds to 30 minutes.

42. A method according to claim 32, wherein step (A) includes the step of introducing into the patient'"'"'s bloodstream a compound including any of a contrast agent, a neuropharmacologic agent, a neuroactive peptides, a protein, an enzyme, a gene therapy agent, a neuroprotective factor, a growth factor, a biogenic amine, a trophic factor to any of brain and spinal transplants, an immunoreactive proteins, a receptor binding protein, a radioactive agent, an antibody, and a cytotoxin.

43. An apparatus for delivering a compound to a selected location in the brain of a patient, the apparatus comprising:

A. an ultrasound source,

B. targeting/delivery means, coupled to the ultrasound source, for applying ultrasound to the selected location in the brain to (i) effect a change at that location detectable by imaging, and (ii) open the blood-brain barrier at that location and, thereby, induce uptake of the compound there, and

C. imaging means for generating a radiologic image of at least a portion of the brain to confirm the location of the change detectable by imaging.

44. An apparatus according to claim 43, wherein targeting/delivery means includes means for delivering the ultrasound through the skull.

45. An apparatus according to claim 44, wherein targeting/delivery means comprises any of a (i) a phased array, (ii) a focused ultrasound transducer, and (iii) a combination of an ultrasound source and acoustic lens.

46. An apparatus according to claim 43, wherein targeting/delivery means includes means for delivering the ultrasound substantially at or beneath exposed dura matter.

47. An apparat us according to claim 43, wherein the imaging means comprises means for generating a radiologic image of at least a portion of the brain in the vicinity of the selected location.

48. An apparatus according to claim 43, wherein the targeting/delivery means includes means for delivering the ultrasound to the selected location in the brain to induce by cavitation a change detectable by imaging and to open the blood-brain barrier.

49. An apparatus according to claim 48, wherein the targeting/delivery means includes means for delivering the ultrasound to the confirmed location in the brain at a frequency ranging from 20 kHz to 10 MHz, sonication duration ranging from 10 nanoseconds to 30 minutes, with continuous wave or burst mode operation, where the burst mode repetition varies from 0.01 Hz to 1 MHz.

50. An apparatus according to claim 43, wherein the targeting/delivery means includes means for delivering the ultrasound to the confirmed location in the brain to induce by heating the change detectable by imaging and to open the blood-brain barrier by heating.

51. An apparatus according to claim 50, wherein the targeting/delivery means includes means for delivering the ultrasound to the confirmed location in the brain at a frequency ranging from 250 kHz to 10 MHz, and with sonication duration ranging from 0.10 microseconds to 30 minutes.

52. A method for delivering a compound from the bloodstream to a selected location in the brain of a patient, the method comprising:

A. applying ultrasound to a selected location in the brain to effect at that location a change detectable by imaging,

B. generating a radiologic image of at least a portion in the brain to confirm the location of that change,

C. further confirming that location by a change in central nervous system function of the patient,

D. applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake of the compound at that location.

53. A method for delivering a compound from the bloodstream to a selected location in the brain of a patient, the method comprising:

A. applying ultrasound to a selected location in the brain to effect a change in a central nervous system function of the patient,

B. confirming that location by a change in that central nervous system function, and

C. applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake of the compound at that location.

54. A method for delivering a compound from the bloodstream to a selected location in the brain, the method comprising:

A. applying ultrasound to a selected location in the brain to (i) induce a change at that location detectable by imaging, and (ii) open the blood-brain barrier at that location and, thereby, induce uptake of the compound at that location,

B. generating a radiologic image of at least a portion in the brain to confirm the location of the change detectable by imaging, and

C. further confirming that location by a change in central nervous system function of the patient.

55. A method for delivering a compound from the bloodstream to a selected location in the brain of a patient, the method comprising:

A. applying ultrasound to a selected location in the brain to (i) a change in a central nervous system function of the patient, and (ii) open the blood-brain barrier at that location and, thereby, induce uptake of the compound at that location, and

B. confirming that location by detecting a change in that central nervous system function.

56. A method for treating at least one of a neurological and a neurologically-related disorder, the method comprising:

A. applying ultrasound to a selected location in the brain to effect at that location a change detectable by imaging,

B. generating a radiologic image of at least a portion in the brain to confirm the location of that change,

C. applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake at that location of a compound in the bloodstream.

57. A method for treating at least one of a neurological and a neurologically-related disorder, the method comprising:

A. applying ultrasound to a selected location in the brain to effect at that location a change detectable by imaging,

B. generating a radiologic image of at least a portion in the brain to confirm the location of that change,

C. applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake at that location of a compound in the bloodstream.

58. A method for modification of neurologic and neurologically-related activity, the method comprising:

A. applying ultrasound to a selected location in the brain to effect at that location a change detectable by imaging,

B. generating a radiologic image of at least a portion in the brain to confirm the location of that change,

C. applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake at that location of a compound in the bloodstream.

59. A method for functional neurosurgery, the method comprising:

A. applying ultrasound to a selected location in the brain to effect at that location a change detectable by imaging,

B. generating a radiologic image of at least a portion in the brain to confirm the location of that change,

C. applying ultrasound to the confirmed location in the brain, or a location based thereon, to open the blood-brain barrier at that location and, thereby, induce uptake at that location of at least a selective cytotoxin in the bloodstream.