Systems and methods for targeted drug delivery

• US 10,322,178 B2
• Filed: 08/11/2014
• Issued: 06/18/2019
• Est. Priority Date: 08/09/2013
• Status: Active Grant

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Chen, Chen, Konofagou, Elisa E., Dayton, Paul
• Primary Examiner(s): Bosques, Edelmira
• Assistant Examiner(s): Swanson, Leah J
• Application Number:
  US14/457,023
• Publication Number:
  US 20150045724A1
• Time in Patent Office: 1,772 Days
• Field of Search: 604 22
• CPC Class Codes: A61B 2017/22008 used or promoted
• CPC Class Codes: A61K 41/0047 Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
• CPC Class Codes: A61N 2007/0039 using microbubbles
• 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

Techniques for opening a target tissue using nanodroplets are provided. An exemplary method can include targeting a region of tissue for opening, delivering a plurality of nanodroplets to the region, and applying an ultrasound beam at the region such that the nanodroplets cavitate, or convert to microbubbles that cavitate, thereby causing the target tissue to open.

Claims

1. A method of delivering a therapeutic agent through a blood vessel having a blood brain barrier to a target location in a brain, comprising:

targeting a region of the blood vessel proximate the target location in the brain;

selecting a plurality of nanodroplets configured to vaporize at an acoustic pressure suitable to open the blood brain barrier with microbubbles, wherein the nanodroplets are separate from the therapeutic agent;

delivering the plurality of nanodroplets to the region;

delivering the therapeutic agent to the region;

applying an ultrasound beam at the region at the acoustic pressure such that the nanodroplets vaporize, or cavitate, or convert to microbubbles that cavitate, thereby causing the blood brain barrier to open and allowing the therapeutic agent to diffuse out of the blood vessel through the open blood brain barrier and to the target location in the brain.

2. The method of claim 1, wherein the therapeutic agent is selected from the group consisting of antibodies, neural stem cells, siRNA, chemotherapeutic molecules, adenoviral vectors and neurotrophic factors.

3. The method of claim 1, wherein the nanodroplets each have a diameter between 100 nm and 300 nm.

4. The method of claim 1, wherein the nanodroplets each have a diameter between 150 nm and 250 nm.

5. The method of claim 1, wherein the ultrasound beam has a sonication pressure greater than 0.45 MPa.

6. The method of claim 1, wherein the ultrasound beam has a sonication pressure greater than 0.6 MPa.

7. The method of claim 1, wherein delivering the nanodroplets comprises at least one injection of the nanodroplets.

8. The method of claim 7, wherein the injection is an intravenous injection.

9. The method of claim 7, wherein the injection is an intraarterial injection.

10. The method of claim 1, wherein delivering the nanodroplets comprises delivering the nanodroplets intranasally.

11. The method of claim 1, wherein delivering the therapeutic agent comprises at least one injection of the therapeutic agent.

12. The method of claim 11, wherein the injection is an intravenous injection.

13. The method of claim 11, wherein the injection is an intraarterial injection.

14. The method of claim 1, wherein delivering the therapeutic agent comprises delivering the therapeutic agent intranasally.

15. The method of claim 1, wherein delivering the nanodroplets and applying the ultrasound beam are performed simultaneously.

16. The method of claim 1, wherein the nanodroplets are a microbubble condensation process.

17. A method of delivering a therapeutic agent through a blood vessel having a blood brain barrier to a target location in a brain of a patient, comprising

delivering the therapeutic agent intranasally;

selecting a plurality of nanodroplets configured to vaporize at an acoustic pressure suitable to open the blood brain barrier with microbubbles, wherein the nanodroplets are separate from the therapeutic agent;

targeting a region of a blood vessel proximate the target location in the brain;

delivering the plurality of nanodroplets into the patient such that the nanodroplets travel to the region of the blood vessel;

applying an ultrasound beam at the region such that the nanodroplets vaporize, or cavitate, or convert to microbubbles that cavitate, thereby generating mechanical effects on the blood vessel and enhancing delivery of the therapeutic agent.

18. The method of claim 17, wherein the mechanical effects include at least one of high shear stress, microstreaming, and microjeting the blood vessel, thereby allowing transvascular delivery of the therapeutic agent.

19. The method of claim 17, wherein the mechanical effects include pushing and pulling surrounding tissue, thereby causing bulk fluid flow in perivascular spaces.

20. The method of claim 17, wherein the ultrasound beam comprises a center frequency of about 1.5 MHz, a peak-negative pressure of about 0.45 MPa, a pulse length of about 6.7 ms, a pulse repetition frequency of about 5 Hz, and a duration of about 1 minute.

21. The method of claim 17, wherein the therapeutic agent is disposed at the target location in the brain at a supra-therapeutic level and the therapeutic agent is disposed elsewhere in the brain at a sub-therapeutic level.

22. The method of claim 17, wherein delivering the nanodroplets and applying the ultrasound beam are performed simultaneously.

23. The method of claim 17, wherein delivering the therapeutic agent and applying the ultrasound beam are performed simultaneously.

24. The method of claim 17, wherein applying the ultrasound beam is performed prior to delivering the therapeutic agent.

25. The method of claim 17, wherein the nanodroplets are delivered intranasally.

26. The method of claim 17, wherein the nanodroplets are generated by a microbubble condensation process.