Microbubble-assisted ultrasound-guided therapy

Patent metadata

Field	Value
Publication number	US-2024269287-A1
Application number	US-202218554944-A
Country	US
Kind code	A1
Filing date	Apr 12, 2022
Priority date	Apr 12, 2021
Publication date	Aug 15, 2024
Grant date	—

Abstract

The innate immune sensing STING pathway has emerged as a potential therapeutic target to boost antitumor immune responses. STING resides in the cytoplasm, and its agonists, such as cGAMP, are dinucleotides that are difficult to deliver intracellularly. Disclosed herein is a microbubble-based platform (Microbubble (MB)-assisted UltraSound (US)-guided Immunotherapy of Cancer (MUSIC)) that can be used for targeted activation of STING, such as for treatment of primary and metastatic tumors.

First claim

What is claimed is:

1 . A method of targeted in vitro or in vivo drug delivery using sonoporation, the method comprising (i) administering to one or more target cells a composition comprising microbubbles loaded with a payload and (ii) administering an ultrasound stimulus to the one or more target cells, wherein the ultrasound stimulus is effective to sonoporate the one or more target cells.

2 . The method of claim 1 , wherein the payload comprises an agonist for activating the Stimulator of Interferon Genes (STING) signaling pathway within the one or more target cells, optionally wherein the agonist is a cyclic dinucleotide.

3 . The method of claim 1 , wherein the payload comprises a cyclic dinucleotide for inducing or enhancing Type 1 Interferon production within one or more cells.

4 . The method of any one of claims 1-3 , wherein the method is an in vivo method comprising administering the microbubble composition and the ultrasound stimulus to a subject.

5 . The method of any one of the preceding claims , wherein the one or more target cells comprise cancer cells.

6 . The method of any one of the preceding claims , wherein the one or more target cells comprise immune cells.

7 . The method of claim 6 , wherein the immune cells comprise professional antigen-presenting cells (APCs).

8 . The method of claim 7 , wherein the APCs comprise macrophages

9 . The method of claim 7 or 8 , wherein the APCs comprise dendritic cells.

10 . The method of any one of the preceding claims , wherein the microbubbles comprise targeting molecules on the external surfaces of the microbubbles, the targeting molecules being effective to bind the one or more target cells.

11 . The method of claim 10 , wherein the targeting molecules comprise antibodies.

12 . The method of claim 10 or 11 , wherein the targeting molecules bind CD11b.

13 . The method of any one of the preceding claims , wherein the ultrasound stimulus is administered at about 1-2 W/cm 2 , optionally with 50% duty cycle.

14 . The method of any one of the preceding claims , wherein the ultrasound stimulus is administered for between about at least about 30-60 seconds.

15 . The method of any one of the preceding claims , wherein the one or more target cells are exposed to the microbubbles for at least about 10 minutes prior to administering the ultrasound stimulus.

16 . The method of any one of the preceding claims , further comprising using ultrasound to visualize the microbubbles prior to applying the ultrasound stimulus effective to sonoporate the cell membrane, wherein the intensity of the ultrasound used to visualize the microbubbles is less than the intensity of the ultrasound stimulus.

17 . The method of any one of the preceding claims , wherein the microbubbles are decorated with spermine, the payload being non-covalently bound to the spermine.

18 . The method of any one of the preceding claims , wherein the microbubbles are decorated with spermine-dextran conjugates, the payload being non-covalently bound to the spermine within the spermine-dextran conjugates.

19 . The method of any one of the preceding claims , wherein the microbubbles comprise gas cores comprising a perfluorocarbon, optionally wherein the perfluorocarbon is decafluorobutane.

20 . The method of any one of the preceding claims , wherein the microbubbles comprise shells comprising phospholipids, optionally wherein the phospholipids comprise one or both of 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC) and 1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine (DSPE) lipids.

21 . The method of any one of the preceding claims , wherein the microbubbles comprise surfactant shells comprising PEGylated molecules.

22 . The method of any one of the preceding claims , wherein the average microbubble size of the microbubble composition is between about 1 μm and about 10 μm.

23 . The method of claim 22 , wherein the average microbubble size of the microbubble composition is between about 1 μm and about 5 μm

24 . The method of claim 23 , wherein the average microbubble size of the microbubble composition is about 3 μm.

25 . The method of any one of claims 1-22 , wherein the microbubbles are primarily nanobubbles.

26 . The method of claim 25 , wherein the microbubbles are entirely nanobubbles.

27 . The method of claim 25 or 26 , wherein the average microbubble size of the microbubble composition is between about 100 nm and 700 nm.

28 . The method of claim 27 , wherein the average microbubble size of the microbubble composition is between about 200 nm and 600 nm.

29 . The method of claim 28 , wherein the average microbubble size of the microbubble composition is between about 300 nm and 500 nm.

30 . The method of any one of the preceding claims , wherein the microbubble composition comprises microbubbles with biodegradable linkers operably positioned between an exterior surface of a shell of the microbubble and the payload, optionally wherein the biodegradable linker is joining a spermine to a dextran or a spermine to another spermine.

31 . The method of any one of the preceding claims , wherein the payload comprises cyclic guanosine monophosphate-adenosine monophosphate (cGAMP).

32 . The method of any one of claims 1, 2, or 4-31 , wherein the method is an in vitro method.

33 . The method of claim 32 , wherein the composition comprising microbubbles is incubated with the one or more target cells at a concentration of at least about 5, 10, 15, 20, 25, or 30 microbubbles/cell.

34 . The method of claim 32 or 33 , wherein the step of administering to the one or more target cells a composition comprising microbubbles comprising mixing the composition with the one or more target cells in solution.

35 . The method of claim 32 or 33 , wherein the one or more target cells are adhered to a surface and wherein the step of administering to the one or more target cells a composition comprising microbubbles comprises exposing the surface to the composition comprising microbubbles such that the one or more cells are positioned over the microbubbles.

36 . A method of treating cancer in a subject in need thereof, the method comprising performing the targeted drug delivery method of any one of claims 4-31 , wherein administering the microbubble composition to the one or more target cells comprises administering the microbubble composition and the ultrasound stimulus to the subject, and wherein the payload comprises a cyclic dinucleotide.

37 . The method of claim 36 , wherein the subject has been diagnosed with cancer.

38 . The method of claim 36 or 37 , wherein the subject has a tumor.

39 . The method of claim 38 , wherein the subject has one or more metastases.

40 . The method of claim 38 , wherein the microbubble composition is administered intratumorally.

41 . The method of any one of claims 36-39 , wherein the microbubble composition is administered systemically.

42 . The method of claim 41 , wherein the microbubble composition is administered intravenously.

43 . The method of claim 41 or 42 , wherein th

Assignees

• Univ Texas

Inventors

• Khorsandi Sina
• Lux Jacques
• Jiang Wen

Classifications

• A61N2007/0039

  using microbubbles · CPC title

• A61N7/00

  Ultrasound therapy (lithotripsy A61B17/22, A61B17/225; massage using supersonic vibration A61H23/00 {; using ultrasound for introducing media into the body A61M37/0092}) · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K47/6925

  the form being a microcapsule, nanocapsule, microbubble or nanobubble · CPC title

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title