Methods of controlling magnetic nanoparticles to improve vascular flow

• US 9,345,498 B2
• Filed: 12/23/2014
• Issued: 05/24/2016
• Est. Priority Date: 11/02/2009
• Status: Active Grant

• Current Assignee: Pulse Therapeutics, Inc. (Euphrates Vascular, Inc.)
• Original Assignee: Pulse Therapeutics, Inc. (Euphrates Vascular, Inc.)
• Inventors: Creighton, Francis M.
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US14/581,775
• Publication Number:
  US 20150374395A1
• Time in Patent Office: 518 Days
• US Class Current: 1/1
• CPC Class Codes: A61B 17/22 Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for dilators A61M29/00
• CPC Class Codes: A61B 17/22012 in direct contact with, or very close to, the obstruction or concrement for removing obstructions in blood vessels by laser A61B18/245
• CPC Class Codes: A61B 2017/00876 magnetic
• CPC Class Codes: A61B 2017/22084 stone- or thrombus-dissolving
• CPC Class Codes: A61B 2017/22094 for crossing total occlusions, i.e. piercing
• CPC Class Codes: A61B 2034/733 arranged only on one side of the patient, e.g. under a table
• CPC Class Codes: A61B 34/73 Manipulators for magnetic surgery
• CPC Class Codes: A61K 38/482 Serine endopeptidases (3.4.21)
• CPC Class Codes: A61K 38/484 Plasmin (3.4.21.7)
• CPC Class Codes: A61K 41/00 Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• CPC Class Codes: A61K 47/6941 the form being a granulate or an agglomerate
• 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: A61N 2/004 specially adapted for a specific therapy
• CPC Class Codes: A61N 2/02 using magnetic fields produced by coils, including single turn loops or electromagnets A61N2/12 takes precedence
• CPC Class Codes: A61N 2/06 using magnetic fields produced by permanent magnets A61N2/12 takes precedence
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C12Y 304/21007 : Plasmin (3.4.21.7), i.e. fibrinolysin
• CPC Class Codes: C12Y 304/21068 : Tissue plasminogen activator (3.4.21.68), i.e. tPA
• CPC Class Codes: H01F 7/0273 : Magnetic circuits with PM for magnetic field generation
• CPC Class Codes: Y10S 977/811 : Of specified metal oxide composition, e.g. conducting or semiconducting compositions such as ITO, ZnOx
• CPC Class Codes: Y10S 977/905 : Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/909 : Obstruction removal

Abstract

Some embodiments provide a system for external manipulation of magnetic nanoparticles in vasculature using a remotely placed magnetic field-generating stator. In one aspect, the systems and methods relate to the control of magnetic nanoparticles in a fluid medium using permanent magnet-based or electromagnetic field-generating stator sources. Such a system can be useful for increasing the diffusion of therapeutic agents in a fluid medium, such as a human circulatory system, which can result in substantial clearance of fluid obstructions, such as vascular occlusions, in a circulatory system resulting in increased blood flow.

Claims

1. A method of increasing fluid flow within vasculature of a subject through external magnetomotive manipulation of magnetic nanoparticles introduced within the vasculature, the method comprising:

introducing a therapeutic agent within vasculature of a subject, the therapeutic agent configured to have a therapeutic effect on a therapeutic target within the vasculature;

administering a plurality of magnetic nanoparticles within the vasculature;

causing a magnet external to the vasculature and having a magnetic field and a directed magnetic gradient to be positioned and to rotate in a manner sufficient to cause the magnetic nanoparticles to collectively form a plurality of agglomerates within the vasculature and to travel within the vasculature toward a therapeutic target in response to the rotating magnetic field and the directed magnetic gradient of the magnet; and

causing the agglomerates to generate a circulating fluid motion proximal to the therapeutic target by setting a rotational frequency of the rotating magnetic field, a plane of the rotating magnetic field with respect to the therapeutic target, and a distance of the rotating magnetic field with respect to the therapeutic target,

wherein the circulating fluid motion facilitates contact of the therapeutic agent with the therapeutic target by enhancing delivery of the therapeutic agent to the therapeutic target, thereby providing more effective interaction of the therapeutic agent with the therapeutic target.

2. The method of claim 1, wherein the therapeutic agent is attached to the magnetic nanoparticles prior to introduction.

3. The method of claim 1, wherein the therapeutic agent is introduced within the vasculature separate from the magnetic nanoparticles.

4. The method of claim 1, wherein the therapeutic agent is a thrombolytic drug.

5. The method of claim 1, wherein the therapeutic target is a clot in a cerebral blood vessel.

6. The method of claim 1, wherein the magnet is a permanent magnet rotatably coupled to at least one motor.

7. The method of claim 1, wherein said causing a magnet external to the vasculature and having a magnetic field and a directed magnetic gradient to be positioned and to rotate comprises causing the motor to position the magnet at an effective distance and an effective plane with respect to the therapeutic target, and to rotate the magnet at an effective frequency.

8. The method of claim 7, wherein the effective frequency is between 1 Hz and 30 Hz.

9. The method of claim 4, wherein the thrombolytic drug is selected from the group consisting of:

tissue plasminogen activator (tPA), plasminogen, streptokinase, urokinase, recombinant tissue plasminogen activators (rtPA), alteplase, reteplase, and tenecteplase.

10. The method of claim 1, wherein the therapeutic target is selected from the group consisting of:

a vein thrombus, an arterial thrombus, and an embolism.

11. A method of increasing fluid flow within a blood vessel of a subject through external magnetomotive manipulation of magnetic nanoparticles introduced within the subject, the method comprising:

introducing a thrombolytic agent within vasculature of a subject, the thrombolytic agent configured to facilitate lysis of a clot within a blood vessel;

administering a plurality of magnetic nanoparticles within the vasculature;

causing a magnet external to the vasculature and having magnetic field and a directed magnetic gradient to be positioned and to rotate in a manner sufficient to cause the magnetic nanoparticles to collectively form agglomerates within the vasculature and to travel within the vasculature toward the clot within the blood vessel in response to the rotating magnetic field and the directed magnetic gradient of the magnet; and

causing the agglomerates to generate a circulating fluid motion proximal to the clot by controlling a frequency of the rotating magnetic field, a plane of the rotating magnetic field with respect to the clot, and a distance of the rotating magnetic field with respect to the clot, thereby increasing contact of the therapeutic agent with the clot.

12. The method of claim 11, wherein the magnet is a permanent magnet rotatably coupled to at least one motor.

13. The method of claim 11, wherein introducing a thrombolytic agent within vasculature of a subject is performed separately from administering the plurality of magnetic nanoparticles within the vasculature.

14. The method of claim 11, wherein the thrombolytic agent is a thrombolytic drug selected from the group consisting of:

tissue plasminogen activator (tPA), plasminogen, streptokinase, urokinase, recombinant tissue plasminogen activators (rtPA), alteplase, reteplase, and tenecteplase.

15. A method of increasing fluid flow within vasculature of a subject through external magnetomotive manipulation of magnetic nanoparticles introduced within the vasculature, the method comprising:

applying a magnetic field and a directed magnetic gradient of a magnet to a plurality of magnetic nanoparticles introduced within vasculature of a subject;

rotating the magnetic field at a first rotational frequency effective to collectively form a plurality of agglomerates in response to the rotating magnetic field and the directed gradient;

rotating the magnetic field at a second rotational frequency effective to move the agglomerates along the vasculature in an end-over-end manner toward a therapeutic target in response to the rotating magnetic field and the directed gradient; and

causing the agglomerates to generate a circulating fluid motion within fluid proximal to the therapeutic target, thereby enhancing delivery of a therapeutic agent to the therapeutic target and facilitating exposure of the therapeutic agent to the therapeutic target in response to the rotating magnetic field and the directed gradient.

16. The method of claim 15, further comprising causing the agglomerates to travel through the blood vessel by repeatedly:

a) walking end over end along the blood vessel away from the magnetic field in response to the rotation of the agglomerates and the directed magnetic gradient; and

b) flowing back through fluid in the blood vessel towards the magnetic field in response to the rotation of the agglomerates and the directed magnetic gradient.

17. The method of claim 15, wherein the therapeutic agent comprises a thrombolytic drug.

18. The method of claim 15, wherein the first rotational frequency and the second rotational frequency are each between 1 Hz and 30 Hz, and wherein the first rotational frequency and the second rotational frequency are different.

19. The method of claim 15, wherein the first rotational frequency and the second rotational frequency are each between 1 Hz and 30 Hz, and wherein the first rotational frequency and the second rotational frequency are the same.

20. The method of claim 15, wherein the agglomerates comprise magnetic nanoparticle rods having a length between one and two millimeters when exposed to a rotating magnetic field having a magnitude of between 0.01 Tesla and 0.1 Tesla that is rotating at a rotational frequency between 3 and 10 Hz and to a magnetic gradient strength of between 0.01 Tesla/meter and 5 Tesla/meter.