Methods, Compositions and Device for Directed and Controlled Heating and Release of Agents

• US 20100068260A1
• Filed: 07/23/2009
• Published: 03/18/2010
• Est. Priority Date: 01/23/2007
• Status: Abandoned Application

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Meares, Claude, Paoli, Eric, Kruse, Dustin E., Day, Jeffrey, Ferrara, Katherine W., Stephens, Douglas N.
• Application Number:
  US12/508,076
• Publication Number:
  US 20100068260A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/55 Protease inhibitors
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings

Abstract

A composition coupled to an agent with a cleavable linker is provided. Specifically, the composition is used for releasing the agent through a temperature-sensitive mechanism at a targeted location in a subject with heat. It is advantageous to applications where there is a need to accurately deploy an agent in a targeted location to reduce adverse side effects or increase efficacy of the agent. A device and method for providing heat at the targeted location in the subject is also provided. The device and method allows release of the agents in a targeted manner and prevents overheating of the targeted location or the tissue surrounding the targeted location. It is advantageous to applications where there is a need to accurately control the temperature in a targeted location in a biological body, for instance, to deploy an agent in the targeted location.

Claims

1. A composition, comprising:

a vehicle comprising one or more layers entrapping a liquid, a solid, or a combination thereof, wherein the one or more layers comprise an interior surface and an exterior surface, and wherein the interior surface contacts the entrapped liquid, solid, or combination thereof;

an agent coupled to the exterior surface via a cleavable linker; and

a cleaving molecule coupled to the exterior surface, wherein the cleavable linker and the cleaving molecule are present in a plurality of distinct domains on the exterior surface at a first temperature, the plurality of distinct domains being capable of mixing upon heating of the composition to a second temperature greater than the first temperature.

2. The composition of claim 1, wherein the second temperature is greater than or equal to a phase transition temperature.

3. The composition of claim 1, wherein the heating of the composition to the second temperature allows for cleavage of the cleavable linker by the cleaving molecule.

4. The composition of claim 1, wherein the one or more layers comprises a phospholipid.

5. The composition of claim 4, wherein the phospholipid is selected from the group consisting of:

dimyristoylphosphatidyl choline, palmitoylmyristoylphosphatidyl choline, myristolypalmitoylphosphatidyl choline, dipalmitoylphosphatidyl choline, stearoylpalmitoylphosphatidyl choline, palmitoylstearolyphosphatidyl choline, distearolyphosphatidyl choline, and synthetic C₁₇ phosphatidyl choline.

6. The composition of claim 1, wherein the cleavable linker comprises a substrate.

8. The composition of claim 1, wherein the cleaving molecule comprises an enzyme.

10. The composition of claim 1, wherein the cleaving molecule comprises a thiol.

11. The composition of claim 1, wherein the second temperature comprises a range of from 38°

C. to 80°

C.

14. The composition of claim 1, wherein the agent is a therapeutic agent.

16. The composition of claim 2, wherein the composition comprises a plurality of distinct vehicles, wherein each distinct vehicle comprises a distinct agent, and wherein each distinct vehicle comprises a distinct phase transition temperature.

17. The composition of claim 1, wherein the heating is directed to a location at which release of the agent is desired.

18. The composition of claim 1, further comprising an indicator, wherein the indicator is for monitoring a thermal treatment efficacy in a tissue, quantifying a release of an agent, quantifying a thermal dose, quantifying a blood flow in a thermally-treated region, quantifying a systemic vehicle concentration, quantifying a systemic concentration of a released agent, or quantifying a ratio of released to intact vehicles.

19. The composition of claim 1, wherein the vehicle is a liposome.

20. The composition of claim 1, wherein the vehicle is a micelle.

22. The composition of claim 1, wherein the one or more layers comprises a lipid bilayer comprising an inner shell and an outer shell, wherein the inner shell comprises the interior surface and the outer shell comprises the exterior surface.

23. The composition of claim 1, wherein the vehicle does not comprise a fatty-acyl peptide, wherein the vehicle is not a microbubble, wherein the vehicle does not comprise a gas, and wherein pressure does not cause mixing of the plurality of distinct domains.

28. A method for treating a subject, comprising:

administering the composition of claim 1 to the subject;

allowing the composition to accumulate in a target site of the subject for a time period;

heating the target site to the second temperature with a heating device; and

releasing the agent from the composition, wherein the agent is released by the cleavage of the cleavable linker by the cleaving molecule.

7. (canceled)

9. (canceled)

12. (canceled)

13. (canceled)

15. (canceled)

21. (canceled)

24. An ultrasound heating device, comprising:

a temperature feedback device that senses a temperature and provides a temperature-dependent signal interpretable by an ultrasound imaging device;

an acoustic pressure feedback device that senses acoustic pressure and provides an acoustic pressure-dependent signal interpretable by the ultrasound imaging device; and

a housing for the temperature and acoustic pressure feedback devices.

25. (canceled)

26. (canceled)

27. (canceled)

29. (canceled)

30. A composition, comprising:

a vehicle comprising one or more layers entrapping a liquid, a solid, or a combination thereof, wherein the one or more layers comprise an interior surface and an exterior surface, and wherein the interior surface contacts the entrapped liquid, solid, or combination thereof;

an agent coupled to the exterior surface via a cleavable linker; and

a cleaving molecule coupled to the interior surface, wherein the cleavable linker is substantially present on the exterior surface at a first temperature, wherein the cleaving molecule is substantially present on the interior surface at the first temperature, and wherein the surfaces are capable of mixing upon heating of the composition to a second temperature greater than the first temperature.

31-50. -50. (canceled)