Medical imaging contrast devices, methods, and systems

Patent metadata

Field	Value
Publication number	US-9265483-B2
Application number	US-201113814623-A
Country	US
Kind code	B2
Filing date	Aug 5, 2011
Priority date	Aug 6, 2010
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

Systems, methods, and devices for generating and using size-selected lanthanide-coated microbubbles for controlling an imaging signal via microbubble fragmentation and for magnetic resonance imaging guided focused ultrasound therapy.

First claim

The invention claimed is:

1. A method of controlling an imaging signal through microbubble fragmentation, comprising:
fabricating and storing microbubbles at a first time, and at a later time, recovering pre-fabricated microbubbles;
introducing pre-fabricated microbubbles into a portion of a host;
bursting the microbubbles using an external acoustic force; and
imaging the portion of the host using an imaging device;
the microbubbles being configured to include a paramagnetic inhomogeneity at a gas-liquid interface when intact, and are further configured such that the paramagnetic inhomogeneity disappears after the bursting of the microbubbles, and
controlling the imaging signal responsively to a state of the microbubbles, the state of the microbubbles being one of an intact and a fragmented state.

2. The method of claim 1 , wherein the imaging includes changing, using a controller, an imaging signal from a negative contrast to a positive contrast responsively to a time of microbubble fragmentation and generating at least one image responsively to at least one of a difference in magnitude of the negative and positive contrast and a rate of change from negative to positive contrast.

3. The method of claim 1 , wherein the imaging includes controlling an imaging signal intensity responsively to a concentration of the fragmented microbubbles.

4. The method of claim 3 , wherein the imaging includes controlling the imaging signal such that the imaging signal intensity increases with an increase of the concentration of the fragmented microbubbles.

5. The method of claim 3 , wherein the controlling is performed responsively to a concentration of a paramagnetic lanthanide bound to a fragmented microbubble membrane.

6. The method of claim 1 , wherein the imaging signal includes a magnetic resonance imaging signal and the imaging device includes one of a magnetic resonance imaging device and an ultrasound imaging device.

7. The method of claim 1 , wherein the microbubbles include a membrane enveloping a fluid, the paramagnetic inhomogeneity being generated by a paramagnetic lanthanide bound to a surface of the membrane.

8. The method of claim 7 , wherein the paramagnetic lanthanide is bound to the surface of the membrane by post-labeling.

9. The method of claim 7 , wherein the membrane includes a lipid coating and the paramagnetic lanthanide is bound to the lipid coated membrane by post-labeling.

10. The method of claim 9 , wherein the post-labeling includes:
functionalizing the membrane with a macrocyclic ligand; and
loading the paramagnetic lanthanide through chelation to the macrocyclic ligand which is conjugated to the membrane.

11. The method of claim 10 , wherein the macrocyclic ligand includes a metal chelating ligand.

12. The method of claim 11 , wherein the metal chelating ligand includes one of a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid monoacid mono(N-hydroxysuccinimide ester) (DOTA-NHS), or a (DTPA).

13. The method of claim 10 , wherein the lipid coated membrane includes 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE).

14. The method of claim 10 , further comprising reacting the macrocyclic ligand with a primary amino group on the lipid coated membrane.

15. The method of claim 7 , wherein the paramagnetic lanthanide includes gadolinium Gd 3+ .

16. The method of claim 1 , wherein the controlling of the image signal includes spatial and temporal control.

17. A method of real-time monitoring of location, intensity and dose of ultrasound energy deposition in a tissue, comprising:
introducing pre-fabricated microbubbles into a portion of a host;
bursting the microbubbles using ultrasound; and
imaging the portion of the host using an imaging device, the imaging including visualizing an ultrasound-induced microbubble destruction on an image generated using magnetic resonance imaging, the microbubbles including a fluid core, a membrane enveloping the fluid core, and a material bound to the membrane which is capable of creating a magnetic inhomogeneity at gas-liquid interfaces of the microbubbles, the pre-fabricated microbubbles being configured such that the magnetic inhomogeneity disappears after the bursting of the microbubbles,
wherein the image changes from a negative to a positive image contrast based on a concentration of material remaining on fragmented microbubble membranes.

18. A method of producing an image, comprising:
creating a magnetic inhomogeneity at gas-liquid interfaces of size-selected lipid-coated microbubbles by post-labeling;
introducing the microbubbles into a portion of a host;
bursting the microbubbles using ultrasound to thereby open a blood-brain-barrier (BBB) in the blood capillary endothelium of the host; and
imaging the blood-brain-barrier opening using an electromagnetic scanner, the imaging including visualizing ultrasound-induced microbubble destruction on an image generated using the electromagnetic scanner,
wherein the image changes from a negative to a positive image contrast based on a concentration of material remaining on fragmented microbubble membranes.

19. A system for producing an image, comprising:
a microbubble generator to generate lipid-coated microbubbles including a membrane enveloping a fluid and a material bound to the membrane, the material being capable of creating a magnetic inhomogeneity at gas-liquid interfaces of the microbubbles;
an ultrasound device to burst the microbubbles after insertion of the lipid-coated microbubbles into a host; and
an imaging device to image a portion of the host after insertion of the lipid-coated microbubbles into the host;
the imaging device being further configured to allow for visualizing ultrasound-induced microbubble destruction,
wherein the image changes from a negative to a positive image contrast based on a concentration of the material remaining on fragmented microbubble membranes.

20. A method of preparing and using a plurality of paramagnetic material-bound lipid microbubbles, comprising:
preparing a plurality of microbubbles, each microbubble including a lipid coated membrane encapsulating a fluid;
inserting the lipid-coated microbubbles into a holding device;
separating the microbubbles having a size within a predetermined size range from the rest of the microbubbles by applying centrifugation on the holding device,
collecting the microbubbles having a size within the predetermined range into a solid concentrate at an upper side of the holding device;
removing the microbubbles that are not in the solid concentrate from the holding device, so as to allow the separated microbubbles to be stored and transported in the holding device;
labeling the separated microbubbles with a paramagnetic material prior to using the microbubbles, wherein the labeling includes:
functionalizing the membranes of the separated microbubbles with a macrocyclic ligand; and
loading the paramagnetic material through chelation to the macrocyclic ligand which is conjugated to the membranes;

inserting the plurality of paramagnetic material-bound lipid microbubbles into a host;
bursting the inserted microbubbles using ultrasound; and
controlling an imaging signal responsively to a state of the microbubbles, the state of the microbubbles being characterizable as one of intact and fragmented.

21. A method of monitoring a location, intensity and/or dose of ultrasound energy deposition in a tissue, comprising:
int

Assignees

• Borden Mark A
• Feshitan Jameel A
• Konofagou Elisa E
• Vlachos Fotios
• Univ Columbia

Inventors

• Borden Mark A
• Feshitan Jameel A
• Konofagou Elisa E
• Vlachos Fotios

Classifications

• A61K49/1809

  Micelles, e.g. phospholipidic or polymeric micelles · CPC title

• A61K49/222

  characterised by a special physical form, e.g. emulsions, liposomes · CPC title

• A61B2019/5236

  Human Necessities · mapped topic

• A61N7/02

  Localised ultrasound hyperthermia · CPC title

• A61N2007/0039

  using microbubbles · CPC title