Diagnostic imaging of lymph structures

• US 6,444,192 B1
• Filed: 02/05/1999
• Issued: 09/03/2002
• Est. Priority Date: 02/05/1999
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Mattrey, Robert F.
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US09/245,828
• Publication Number:
  US 20020061280A1
• Time in Patent Office: 1,306 Days
• Field of Search: 424/9.52, 424/9.51, 424/9.5, 600/458, 600/441
• US Class Current: 424/9.52
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/225 Microparticles, microcapsules gas-filled to be classified in A61K49/223
• CPC Class Codes: Y10S 977/928 X-ray agent
• CPC Class Codes: Y10S 977/929 Ultrasound contrast agent

Abstract

In accordance with the present invention, there are provided methods for identifying the sentinel lymph node in a drainage field for a tissue or organ in a subject. In select embodiments, the invention allows for the identification of the first or sentinel lymph node that drains the tissue or organ, particularly those tissues associated with neoplastic or infectious diseases and disorders, and within the pertinent lymph drainage basin. Once the drainage basin from the tissue or organ, i.e., the sentinel lymph node, is identified, a pre-operative or intraoperative mapping of the affected lymphatic structure can be carried out with a contrast agent. Identification of the first or sentinel lymph node, on the most direct drainage pathway in the drainage field, can be accomplished by a variety of imaging techniques, including ultrasound, MRI, CT, nuclear and others. Moreover, once the lymphatic structure is identified as being associated with neoplastic or infectious diseases and disorders, the affected lymphatic structure can be removed surgically or by a suitable minimally invasive procedure to allow pathological analysis to be performed to determine whether certain diseases or disorders exist, without resort to more radical lymphadenectomy. Further, the agent can be made to carry diagnostic or therapeutic probes to be activated and/or delivered to the injection site or any part of the lymphatic pathway downstream from the injection site.

Claims

1. A method for diagnosing a lymphatic disorder of one or more lymph structures in a subject, said method comprising:

administering in the region of one or more lymph structures of said subject a diagnostically effective amount of a particulate ultrasound contrast agent, said contrast agent having a mean particle size in the range of about 1 micron up to about 10 microns in diameter, wherein said contrast agent is administered subcutaneously or intramuscularly such that at least a portion of said contrast agent enters the lymphatic circulation of the subject;

imaging said subject using ultrasound whereby at least one regional lymph structure is detected on the image by measuring said contrast agent in the lymphatic circulation, and

detecting the lymphatic disorder by comparing the image of the at least one regional lymph structure with that of a normal lymph structure.

2. A method according to claim 1, wherein said contrast agent is administered so as to localize in or pass through the lymphatic circulation.

3. A method according to claim 2, wherein said method further comprises massaging the site of administration or stimulating the site of administration by exercise or by applying ultrasound.

4. A method according to claim 1, wherein said particulate contrast agent comprises a microbubble preparation having dispersed therein a plurality of microbubbles.

5. A method according to claim 4, wherein said microbubbles comprise a fluorocarbon gas or gas precursor.

6. A method according to claim 1, wherein said ultrasound imaging comprises harmonic ultrasound imaging.

7. A method according to claim 1, wherein said contrast agent carries a labeling substance that is released at any site from the point of administration to any portion of a lymphatic chain.

8. A method according to claim 1, wherein said contrast agent carries a therapeutic substance to treat or effect a target tissue at the site of administration or anywhere along the lymphatic circulation.

9. A method according to claim 1, wherein the at least one lymph structure is downstream from tissue that is neoplastic or suspected to be neoplastic.

10. A method according to claim 1, wherein said contrast agent is modified to promote macrophage uptake.

11. The method of claim 1, wherein the lymphatic disorder is selected from a lymphatic metastasis of cancer, a lymphoma, and a lymph node hyperplasia.

12. The method of claim 7, wherein the contrast agent is activated or made to release its contents into the lymphatic circulation by applying an external energy.

13. The method of claim 12, wherein the external energy is mechanical or ultrasonic.

14. A method for detecting a sentinel lymph node in a subject, said method comprising:

administering to tumor-bearing tissue of said subject a diagnostically effective amount of a particulate ultrasound contrast agent comprising a plurality of microbubbles having a mean particle size in the range of about 1 micron up to about 10 microns in diameter, wherein the contrast agent is administered intramuscularly, subcutaneously, dermally, transdermally, intraepidermally or intraparenchymally and wherein at least a portion of the contrast agent passes from the site of administration to enter into the lymphatic circulation of the subject; and

imaging said subject using ultrasound so as to detect the lymph node nearest the tumor in the tumor bearing tissue.

15. A method according to claim 14, wherein said plurality of microbubbles comprise a fluorocarbon gas or gas precursor.