SYSTEMS, COMPOSITIONS, AND METHODS FOR LOCAL IMAGING AND TREATMENT OF PAIN

• US 20090030308A1
• Filed: 03/21/2008
• Published: 01/29/2009
• Est. Priority Date: 09/21/2005
• Status: Active Grant

• Current Assignee: California Polytechnic State University (California State University System)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Bradford, David S., Lotz, Jeffrey C.
• Granted Patent: US 9,161,735 B2
• Time in Patent Office: Days
• US Class Current: 600/431
• CPC Class Codes: A61B 18/14 Probes or electrodes therefor
• CPC Class Codes: A61B 2018/00339 Spine, e.g. intervertebral disc
• CPC Class Codes: A61B 2018/00577 Ablation
• CPC Class Codes: A61B 2018/00642 with feedback, i.e. closed loop control
• CPC Class Codes: A61B 5/4041 Evaluating nerves condition
• CPC Class Codes: A61B 5/4824 Touch or pain perception evaluation A61B5/4821 takes precedence
• CPC Class Codes: A61B 6/506 for diagnosis of nerves
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 51/1096 radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
• CPC Class Codes: A61M 2230/005 Parameter used as control input for the apparatus
• CPC Class Codes: A61M 5/007 for contrast media
• CPC Class Codes: A61M 5/1723 using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00
• CPC Class Codes: A61N 7/02 Localised ultrasound hyperthermia hyperthermia in general A61F7/00
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Pain factors are labeled with targeted agents or markers delivered into the body. The labeled pain factors are imaged with appropriate imaging tools in a manner allowing selective identification and localization of areas of pain source or transmission. The labeled pain factors allow spatial differentiation in the imaging sufficient to specify the location of the pain so as to drive therapeutic decisions and techniques in order to treat the pain. Pain factors labeled and imaged in this manner may include one or more of nerve factors, blood vessel factors, cellular factors, and inflammation factors. Labeled markers may include for example radioactive materials (e.g. tritiated or iodinated molecules) or other materials such as metal (e.g. gold) nanoparticles. Intermediary binding materials may be used, such as for example bi-specific antibodies. Therapeutic components of the system and method include for example localized energy delivery or ablation treatments, or local drug or other chemical delivery. Locations containing pain factor selectively bound by targeted agents are selectively treated with directed energy into a region containing the targeted agent bound to the pain factor.

Claims

1. A method for conducting a medical procedure related to a localized, active source of pain at a location associated with a region of tissue in a patient, comprising:

artificially labeling a pain factor at the location in a manner substantially increasing the ability to image the pain factor with an imaging tool; and

imaging the labeled pain factor in a manner sufficient to selectively differentiate a first concentration of the labeled pain factor at the location versus a second concentration of the labeled pain factor in tissue adjacent to the location.

2. The method of claim 1, further comprising:

delivering a substantially targeted agent that comprises a targeted label into the patient that is adapted to differentially bind to and label a pain factor associated with the source of pain at the location; and

artificially labeling the pain factor at the location by binding the pain factor with the targeted label.

3. The method of claim 1, wherein the pain factor comprises:

at least one of a nerve factor, a blood vessel factor, a cellular factor, an inflammatory factor, or a combination thereof.

4. The method of claim 3, wherein the pain factor comprises a nerve factor that comprises at least one substance associated with at least one of a nerve fiber or a cellular structure associated with the nerve fiber.

5. The method of claim 1, wherein the pain factor comprises a blood vessel factor that comprises at least one of a blood vessel or a substance or structure associated with the blood vessel.

6. The method of claim 5, wherein the blood vessel factor comprises a substance or structure associated with microvessels.

7. The method of claim 3, wherein the pain factor comprises a cellular factor that is associated with at least one inflammatory factor, a cell that produces at least one inflammatory factor, a cell that is actively producing an inflammatory factor, or an inflammatory cell of a type that is attracted to a second pain factor at the location.

8. The method of claim 7, wherein the pain factor comprises a leukocyte.

9. The method of claim 3, wherein the pain factor comprises a cytokine.

10. The method of claim 1, wherein the pain factor comprises substance P, CGRP, trka, nerve growth factor (NGF), NGF antagonist, PGP 9.5, SYN, peripherin, Neurofilament 200 kD (NF200), TNF-α

, infliximab, PECAM, CD34, GFAP, interleukin, PGE-2, or an analog or derivative or binding agent or antibody thereof.

11. The method of claim 1, wherein the pain factor comprises a nerve binding agent or antibody.

12. The method of claim 1, wherein the pain factor comprises a TNF-α

blocker.

13. The method of claim 1, wherein the pain factor comprises an interleukin that comprises IL-1, IL-6, or IL-8, or an analog or derivative thereof.

14. The method of claim 1, wherein the pain factor comprises a factor associated with pH in tissue or a binding agent or antibody thereof.

15. The method of claim 14, wherein the labeled pain factor is indicative of a relatively low pH below a predetermined threshold at the location.

16. The method of claim 1, wherein the pain factor comprises a factor associated with pO2 in tissue or a binding agent or antibody thereof.

17. The method of claim 16, wherein the labeled pain factor is indicative of a relatively low pO2 at the location.

18. The method of claim 2, wherein the targeted label comprises:

at least one of a nerve factor, a blood vessel factor, a cellular factor, an inflammatory factor, or a binding agent or an antibody thereof.

19. The method of claim 8, wherein the targeted label comprises a nerve factor that comprises at least one substance associated with at least one of a nerve fiber or a cellular structure associated with the nerve fiber or a binding agent or an antibody thereof.

20. The method of claim 18, wherein the targeted label comprises a blood vessel factor that comprises a substance associated with a structure of a blood vessel, or a microvessel, or a binding agent or an antibody thereof.

21. The method of claim 18, wherein the targeted label comprises a cellular factor that is associated with at least one inflammatory factor, or a cell that produces or is actively producing at least one inflammatory factor, or an inflammatory cell of a type that is attracted to the pain factor at the location, or a binding agent or an antibody thereof.

22. The method of claim 21, wherein the cellular factor comprises a leukocyte, or a binding agent or an antibody thereof.

23. The method of claim 21, wherein the cellular factor comprises a cytokine binding agent or antibody.

24. The method of claim 2, wherein the targeted label comprises a Substance P binding agent or antibody, or a CGRP binding agent or antibody, or a trka binding agent or antibody, or an anti-trkA antibody or binding agent or antibody thereof.

25. The method of claim 2, wherein the targeted label comprises nerve growth factor (NGF), or a NGF antagonist, or nerve binding agent or antibody thereof, or an analog or derivative thereof.

26. The method of claim 2, wherein the targeted label comprises a NGF binding agent or an anti-NGF antibody.

27. The method of claim 2, wherein the targeted label comprises an NGF antagonist binding agent or an anti-NGF antagonist antibody.

28. The method of claim 2, wherein the targeted label comprises PGP 9.5, SYN, peripherin, Neurofilament 200 kD (NF200), TNF-α

, or infliximab, or an analog or derivative thereof, or a binding agent or an antibody thereof.

29. The method of claim 2, wherein the targeted label comprises a TNF-α

blocker.

30. The method of claim 2, wherein the targeted label comprises a PECAM binding agent or antibody, a CD34 binding agent or antibody, a GFAP binding agent or antibody, or an interleukin binding agent or antibody.

31. The method of claim 30, wherein the targeted label comprises an interleukin binding agent or antibody that comprises an IL-1, IL-6, or IL-8 binding agent or antibody.

32. The method of claim 2, wherein the targeted label comprises a PGE-2 binding agent or antibody, or a factor associated with pH or pO2 in tissue or a binding agent or antibody thereof.

33. The method of claim 32, wherein the labeled pain factor is indicative of a relatively low pH below a predetermined threshold at the location.

34. The method of claim 32, wherein the labeled pain factor is indicative of a relatively low pO2 at the location.

35. The method of claim 2, wherein the targeted label comprises a radioactive material.

36. The method of claim 35, wherein the targeted label comprises a radio-labeled TNF-α

antibody or an analog or derivative thereof, or radiolabeled iodine.

37. The method of claim 36, wherein the targeted label comprises a radiolabeled iodine that comprises I-125.

38. The method of claim 1, further comprising imaging the labeled pain factor using an imaging tool that comprises a phosphor imaging plate.

39. The method of claim 2, further comprising:

delivering a first binding agent into the body that is adapted to bind to a first pain factor;

delivering that targeted label into the patient'"'"'s body after the first binding agent is bound to the first pain factor; and

wherein the targeted label is adapted to bind to a site located on the bound combination of the first binding agent and the first pain factor.

40. The method of claim 39, wherein:

the first binding agent comprises a bi-specific antibody with a first binding site adapted to bind to the first pain factor and a second binding site adapted to bind to the targeted label.

41. The method of claim 2, wherein:

the targeted label comprises a cell bound to an antibody or binding agent having an exposed binding site that is adapted to bind to the pain factor.

42. The method of claim 1, further comprising:

conducting a therapeutic procedure in a substantially localized manner to the location where the targeted labeled pain factor is locally imaged.

43. The method of claim 42, wherein the therapeutic procedure is adapted to substantially alleviate generation or transmission of pain at the location.

44. The method of claim 42, wherein the therapeutic procedure is adapted to substantially ablate at least one nerve at the location.

45. The method of claim 42, wherein the therapeutic procedure comprises delivering at least one therapeutic chemical in a substantially localized manner to the location.

46. The method of claim 42, wherein the therapeutic procedure comprises:

delivering a therapeutic dose of energy in a substantially localized manner to the location.

47. The method of claim 46, wherein the therapeutic procedure further comprises:

ablating at least one nerve at the location with the therapeutic dose of energy.

48. The method of claim 46, wherein the therapeutic procedure further comprises:

delivering ultrasound energy to the location.

49. The method of claim 48, further comprising:

delivering the ultrasound energy in a directed manner locally into the location from a second location.

50. The method of claim 49, wherein:

the second location is outside of the patient; and

the ultrasound energy is delivered via high intensity focused ultrasound (HIFU) that is adapted to focus the ultrasound energy to the location.

51. The method of claim 49, wherein:

the second location is adjacent to the location within the patient; and

the ultrasound energy is delivered via a directional ultrasound probe.

52. The method of claim 51, wherein:

the second location is adjacent to an intervertebral disc and the location receiving the directional ultrasound therapy is within the intervertebral disc.

53. The method of claim 46, wherein the therapeutic dose of energy comprises thermal, electrical, microwave, or light energy.

54. The method of claim 53, further comprising delivering the therapeutic dose of electrical energy via a radiofrequency (RF) probe.

55. The method of claim 1, wherein the location comprises at least a portion of an intervertebral disc.

56. The method of claim 1, wherein the location comprises a region of tissue located within only a portion that is equal to less than an entire circumference of an intervertebral disc.

57. The method of claim 56, wherein the portion comprises a region of tissue located within less than or equal to one-half or one-quarter of the circumference of the intervertebral disc.

58. The method of claim 1, wherein the location comprises an end-plate associated with a vertebral body.

59. The method of claim 2, further comprising:

delivering the targeted label in a localized manner to the location.

60. The method of claim 59, further comprising:

injecting the targeted label into a region of tissue associated with the location using a local injection assembly.

61. The method of claim 2, further comprising:

delivering the targeted label systemically to the patient.

62. The method of claim 61, further comprising:

injecting the targeted label into the patient'"'"'s systemic blood circulation.

63. The method of claim 61, further comprising:

delivering the targeted label into the patient'"'"'s gastrointestinal system.

64. The method of claim 2, further comprising:

artificially labeling the pain factor at multiple said locations by binding the pain factor with the targeted label delivered into the patient; and

imaging the labeled pain factor with an imaging tool adapted to image at least one of the targeted label or the labeled pain factor and in a manner sufficient to differentiate a first concentration of the labeled pain factor at the multiple said locations versus a second concentration of the labeled pain factor in tissue adjacent to the multiple said locations.

65. The method of claim 64, further comprising:

conducting at least one therapeutic procedure in a substantially localized manner to each of the locations where the targeted labeled pain factor is locally and selectively imaged.

66. The method of claim 1, wherein the pain factor comprises MIF or a binding agent or antibody thereof.

67. The method of claim 1, wherein the targeted agent comprises an MIF binding agent or antibody.

68. The method of claim 1, wherein the targeted agent comprises a nanoparticle.

69. The method of claim 1, wherein the targeted agent comprises at least one of gold or iron oxide.

70. The method of claim 1, wherein the targeted agent comprises an MRI contrast agent.

71. The method of claim 70, wherein the MRI contrast agent comprises gadolinium.

72. The method of claim 70, further comprising MRI imaging an area of increased concentration of the MRI contrast agent bound to the pain factor.

73. The method of claim 1, wherein the targeted agent comprises an ultrasound contrast agent.

74. The method of claim 73, further comprising ultrasonically imaging an area of increased concentration of the ultrasound contrast agent bound to the pain factor.

75. The method of claim 1, wherein the targeted agent comprises a radiographic contrast agent.

76. The method of claim 75, further comprising imaging an area of increased concentration of the radiographic contrast agent bound to the pain factor using X-ray.

77. The method of claim 1, further comprising imaging a location of the targeted agent bound to the pain factor in a manner allowing for enhanced localized therapy to the location.

78. The method of claim 1, further comprising delivering the targeted agent into the patient via the patient'"'"'s respiratory system.

79. A system for treating pain at a location within a body of a patient, comprising:

a targeted agent that comprises a targeted label that is adapted to bind to and label a pain factor associated with a source of pain at the location;

a delivery assembly that is adapted to deliver the targeted label into the patient;

an imaging system that is adapted to image at least one of the targeted label or the labeled pain factor and in a manner sufficient to selectively differentiate a first concentration of the labeled pain factor at the location versus a second concentration of the labeled pain factor in tissue adjacent to the location; and

a therapeutic device assembly that is adapted to provide therapy in a substantially localized manner that is substantially isolated to the location.

80. A method of performing a medical procedure on a patient, comprising:

delivering a material to a region within a body of a patient;

wherein the material has a preferential binding affinity to a pain factor located within the region sufficient to preferentially bind to the pain factor versus other structures within the region, and such that the material accumulates at a higher concentration within a first portion of the region having a higher amount of the pain factor than other portions within the region; and

after delivering the material to the region, delivering energy to the region in a manner that selectively treats the first portion versus the other portions and such that pain is reduced in the region.

81. A system for treating a patient, comprising:

a volume of material that comprises a metal;

wherein the material exhibits a binding affinity to a pain factor such that when the material is delivered to a region within a body of a patient that includes the pain factor the material differentially binds to the pain factor with more affinity than to other structures within the region, and such that the material accumulates at a higher concentration within a first portion of the region having a higher amount of the pain factor than other portions within the region; and

an energy source that is adapted to deliver energy to the region in a manner that substantially locally treats the first portion versus the other portions.

82. A method for preparing a system for performing a medical procedure on a patient, comprising:

diagnosing the patient with pain;

based upon the diagnosis, preparing a volume of a targeted agent for delivery into the patient; and

wherein the prepared dose of targeted agent is configured to differentially bind to a pain factor associated with the pain in a manner adapted to enhance at least one of (i) diagnostic localization of the pain and (ii) selective tissue therapy in an area associated with the bound pain factor in response to a delivered energy to the area.

83. A system for performing a medical procedure on a patient, comprising:

a volume of a targeted agent prepared for delivery into a patient diagnosed with pain; and

wherein the targeted agent is configured to differentially bind to a pain factor associated with the pain in a manner adapted to enhance at least one of (i) diagnostic localization of the pain and (ii) selective tissue therapy to a location containing the bound pain factor in response to a delivered energy to an area containing the location.

84. A method for selectively treating one or more tissue regions associated with pain in a patient, comprising:

delivering a targeted agent into the patient configured to differentially bind to a pain factor associated with the pain;

allowing the delivered targeted agent to differentially bind to the pain factor so as to form a differentially bound pain factor;

delivering energy into the patient in a manner that differentially treats the one or more regions associated with the differentially bound pain factor.

85. A system for selectively treating one or more tissue regions associated with pain in a patient, comprising:

a volume of targeted agent;

an energy delivery system;

wherein the energy delivery system is configured to deliver energy into the patient; and

wherein the volume of targeted agent is configured for delivery into a patient and to differentially bind to a pain factor associated with the pain in a manner such that tissue regions containing a first concentration of the differentially bound pain factor exhibit a differential and selective therapeutic response to the delivered energy versus other regions with lower concentrations of the differentially bound pain factor.