Nanobubbles useful as an ultrasonic contrast agent for the lymphatic system

• US 8,486,444 B2
• Filed: 08/15/2011
• Issued: 07/16/2013
• Est. Priority Date: 08/13/1999
• Status: Expired due to Term

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Ottoboni, Thomas B., Short, Robert E., Gabe, Jeffrey D.
• Primary Examiner(s): HUI, SAN MING R
• Application Number:
  US13/209,917
• Publication Number:
  US 20120034170A1
• Time in Patent Office: 701 Days
• Field of Search: 424/450, 424/489, 424/9.51
• US Class Current: 424/450
• 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: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres

Abstract

A composition is provided accompanying nanoparticles having diameters in the range of about 100 to 800 nanometers with hollow cores and outer shells with mechanical properties such that they rupture on exposure to predetermined ultrasound energy. The composition is useful for identifying sentinel lymph nodes.

Claims

1. A composition comprising a plurality of nanobubbles comprising a bilayered shell, wherein a majority of said plurality of nanobubbles have diameters in the range of about 100 to 800 nanometers, wherein said bilayered shell comprises an inner polymer layer and an outer cross-linked amphiphillic material layer enclosing a single gas-filled hollow core, wherein the said bilayered shell is rupturable upon exposure to ultrasound energy, and wherein the inner and outer layers are not covalently linked to one another.

2. The composition according to claim 1, wherein said gas is selected from the group consisting of air, a perfluorocarbon and nitrogen.

3. The composition according to claim 2, wherein said gas is nitrogen.

4. The composition according to claim 1, wherein said outer layer further comprises a surface-modifying agent.

5. The composition according to claim 4, wherein said surface-modifying agent is a targeting moiety for binding to a selected tissue.

6. The composition according to claim 4, wherein said surface-modifying agent is a polyethylene glycol.

7. The composition according to claim 1, wherein said cross-linked amphiphilic material is glutaraldehyde cross-linked human serum albumin, said biodegradable polymer is polylactide and said gas is nitrogen.

8. The composition according to claim 1 which further comprises a surfactant.

9. The composition according to claim 1, wherein said biodegradable polymer is selected from the group consisting of polycaprolactone, polylactide, polyglycolide, polyhydroxyvalerate, polyhydroxybutyrate, or copolymers thereof;

delta-valerolactone, polyalkylcyanoacrylates, polyamides, polydioxanones, poly-beta-aminnoketones, polyanhydrides, poly-(ortho)esters, and polyamino acids.

10. The composition according to claim 9, wherein said biodegradable polymer is polylactide.

11. The composition according to claim 8, wherein said surfactant is selected from the group consisting of polyoxyalkylene fatty acid esters and poloxamers.

12. The composition according to claim 1 which further comprises a sugar.

13. The composition according to claim 12, wherein said sugar is selected from the group consisting of mannitol, sucrose, lactose and sorbitol.

14. The composition according to claim 1 which further comprises a synthetic water soluble polymer.

15. The composition according to claim 14, wherein said synthetic water-soluble polymer is selected from the group consisting of polyethylene glycol, polyvinyl pyrrolidone and dextran.

16. The composition according to claim 1 which further comprises an amino acid.

17. The composition according to claim 16, wherein said amino acid is selected from the group consisting of glycine, arginine and aspartic acid.

18. The composition according to claim 1, wherein the intensity and frequency of said ultrasound energy are suitable for ultrasound imaging.

19. The composition according to claim 1, wherein said cross-linked amphiphilic material is cross-linked protein.

20. The composition according to claim 19, wherein said protein is selected from the group consisting of collagen, gelatin, albumin, globulins, and derivatives and combinations thereof.

21. The composition according to claim 20, wherein said protein is albumin.

22. The composition according to claim 1, wherein said cross-linked amphiphilic material is cross-linked with a cross-linking agent selected from the group consisting of an aldehyde and a carbodiimide.

23. The composition according to claim 22, wherein said cross-linking agent is glutaraldehyde.

24. The composition according to claim 4, wherein the surface-modifying agent is a biomaterial that enhances uptake of said plurality of nanobubbles by the lymph system.

25. The composition according to claim 24, wherein said biomaterial is Immunoglobulin G.

26. A composition useful for ultrasound imaging, comprising a plurality of nanobubbles, a majority of which have diameter in the range of about 100 to 800 nanometers, each of which comprises a bilayered shell surrounding a hollow core that is filled with a gaseous contrast agent, wherein the inner layer of the bilayered shell comprises a biodegradable polymer, the outer layer of the bilayered shell comprises a cross-linked amphiphilic material, the inner and outer layers of the bilayered shell are not covalently linked to one another, and further wherein said plurality of nanobubbles do not include a drug or additional contrast agents.