Compound delivery using high-pressure impulse transients

• US 5,658,892 A
• Filed: 02/07/1995
• Issued: 08/19/1997
• Est. Priority Date: 01/15/1993
• Status: Expired due to Fees

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Anderson, Therese M., Doukas, Apostolos G., Flotte, Thomas J., McAuliffe, Daniel J.
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): Lee, Howard C.
• Application Number:
  US08/385,043
• Time in Patent Office: 924 Days
• Field of Search: 514/44, 536/22.1, 536/23.1, 204/155, 204/157.15, 204/157.6, 607/72
• US Class Current: 514/44.00R
• CPC Class Codes: A61B 18/20 using laser
• CPC Class Codes: A61B 18/26 for producing a shock wave, e.g. laser lithotripsy
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/409 having four such rings, e.g. porphine derivatives, bilirubin, biliverdine hemin, hematin A61K31/555
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
• CPC Class Codes: A61N 1/40 Applying electric fields by inductive or capacitive coupling microwave apparatus A61N5/00; Applying radio-frequency signals
• 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
• CPC Class Codes: C12M 35/02 Electrical or electromagnetic means, e.g. for electroporation or for cell fusion
• CPC Class Codes: C12N 13/00 Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation

Abstract

A method of increasing delivery of a compound from an exterior region to an interior region of a cell without causing substantial lethality to the cell. The method includes the steps of first providing the compound in the exterior region proximal to a membrane of the cell, and then exposing the membrane to a time-dependent impulse transient characterized by a rise time and a magnitude. In this manner, the exposing step temporarily increases the permeability of the membrane, resulting in an increase in the diffusion of the compound from the exterior region to the interior region thereby enhancing the delivery of the compound without causing substantial lethality to the cell.

Claims

1. A method of increasing delivery of a compound from an exterior region to an interior region of a cell, said method comprising:

providing the compound in the exterior region proximal to a membrane of the cell, and

exposing the membrane to a time-dependent impulse transient characterized by a rise time with a time constant of between 1 and 150 nanoseconds, and a magnitude of between 1 and 500 bars, wherein said exposing temporarily increases the permeability of the membrane to increase diffusion of the compound from the exterior region to the interior region, thereby enhancing the delivery of the compound to the cell.

2. The method of claim 1, wherein said exposing further includes generating the impulse transient in the exterior region of the cell, and then allowing the impulse transient to propagate until incident on the cell membrane.

3. The method of claim 2, wherein said generating comprises impulsively exciting the exterior region using a rapid, time-dependent force.

4. The method of claim 3, wherein the time-dependent force results from thermoelastic expansion of the exterior region.

5. The method of claim 4, wherein said generating comprises depositing over a short time period an amount of heat in the exterior region, said heat resulting in thermal expansion to cause the time-dependent force.

6. The method of claim 5, wherein the heat is generated using a pulsed optical source emitting a wavelength which is absorbed by a portion of the exterior region.

7. The method of claim 6, wherein the pulsed optical source is a laser.

8. The method of claim 3, wherein the rapid, time-dependent force is generated using a transducer.

9. The method of claim 8, wherein the transducer is in direct contact with the exterior region, and undergoes rapid displacement following application of an optical, thermal, or electric field to generate the impulse transient.

10. The method of claim 9, wherein the transducer is ablated using the applied optical field to cause the rapid displacement.

11. The method of claim 9, wherein the transducer undergoes piezoelectric expansion following application of the electrical field to cause the rapid displacement.

12. The method of claim 9, wherein the transducer undergoes thermal expansion following application of heat or a plasma to cause the rapid displacement.

13. The method of claim 1, wherein the time constant is below 35 nanoseconds.

14. The method of claim 1, wherein the pressure is between 250 and 350 bars.

15. The method of claim 1, wherein multiple impulse transients are used during said exposing step.

16. The method of claim 1, wherein said providing comprises directly applying the compound to the exterior region proximal to the cell.

17. The method of claim 16, wherein the compound is applied to a solution in the exterior region, and the cell is exposed to the impulse transient in vitro.

18. The method of claim 1, wherein said providing comprises administering the compound to a patient prior to said exposing, and the cells are exposed to the impulse transient in vivo.

19. The method of claim 18, wherein the patient is a human patient.

20. The method of claim 19, wherein the patient has a genetic disease.

21. The method of claim 1, wherein said exposing is extracorporeal.

22. The method of claim 1, wherein said exposing is during invasive surgery.

23. The method of claim 1, wherein the cell is a diseased cell comprised in a region of diseased tissue.

24. The method of claim 22, wherein the compound has a delivery index of at least 50, and the impulse transient is administered when a level of the compound in a region of healthy tissue is less than 50 percent of the level of said compound present in the diseased tissue.

25. The method of claim 1, wherein the compound comprises nucleic acid.

26. The method of claim 25, wherein said nucleic acid is DNA.

27. The method of claim 25, wherein the nucleic acid is RNA.

28. The method of claim 26, wherein the DNA comprises a gene.

29. The method of claim 1, wherein the cell is a member of a population of cells exposed to said time-dependent impulse transient.

30. The method of claim 28, wherein the compound is a non-cytotoxic compound, and a substantial fraction of the population remains viable following said exposing.

31. The method of claim 1, wherein more that one compound is delivered to the cell.