Uniform field magnetization and targeting of therapeutic formulations

• US 20090082611A1
• Filed: 05/01/2008
• Published: 03/26/2009
• Est. Priority Date: 02/20/2004
• Status: Active Grant

• Current Assignee: Children's Hospital of Philadelphia (Children's Hospital of Philadelphia Foundation)
• Original Assignee: Children's Hospital of Philadelphia (Children's Hospital of Philadelphia Foundation)
• Inventors: Fishbein, Ilia, Levy, Robert J., Alferiev, Ivan, Polyak, Boris, Friedman, Gennady, Chorny, Michael, Williams, Darryl
• Granted Patent: US 8,562,505 B2
• Time in Patent Office: Days
• US Class Current: 600/9
• CPC Class Codes: A61K 31/203 Retinoic acids ; Salts thereof
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 35/44 Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
• CPC Class Codes: A61K 35/761 Adenovirus
• 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 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/6455 Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
• CPC Class Codes: A61K 47/6923 the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 47/6929 the form being a nanoparticle, e.g. an immuno-nanoparticle
• CPC Class Codes: A61K 48/0008 characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
• CPC Class Codes: A61K 48/0041 the non-active part being polymeric
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61K 9/5094 Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
• CPC Class Codes: A61K 9/5115 Inorganic compounds
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• 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: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5169 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/5192 : Processes
• CPC Class Codes: C12N 15/111 : General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/86 : Viral vectors
• CPC Class Codes: C12N 2320/32 : Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12N 2710/10343 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2710/10345 : Special targeting system for viral vectors

Abstract

Systems and methods for magnetic targeting of therapeutic particles are provided. Therapeutic particles comprise one or more magnetic or magnetizable materials and at least one therapeutic agent. Therapeutic particles are specifically targeted using uniform magnetic fields capable of magnetizing magnetizable materials, and can be targeted to particular locations in the body, or can be targeted for capture, containment, and removal. Also provided are bioresorbable nanoparticles prepared without the use of organic solvents, and methods for therapeutically using such bioresorbable nanoparticles.

Claims

1. A system for magnetically targeting therapeutic particles comprising:

(a) a particle comprising at least one therapeutic agent and a first magnetic or magnetizable material;

(b) an implantable device comprising a second magnetic or magnetizable material; and

,

(c) a retrieval system comprising a third magnetic or magnetizable material capable of being reversibly connected to a subject.

2. The system of claim 1, further comprising a magnetic field generator configured to generate a uniform magnetic field capable of magnetizing magnetizable material, wherein the uniform magnetic field generates at least one directable magnetic field gradient, wherein the gradient directs the particle to the device and directs any spent particles or particles that are not delivered to the device to the retrieval system.

3. The system of claim 2, wherein the gradient is generated proximal to the device.

4. The system of claim 2, wherein the gradient is generated proximal to the retrieval system.

5. The system of claim 1, wherein the at least one therapeutic agent comprises a pharmaceutical, biomolecule, or cell.

6. The system of claim 5, wherein the biomolecule is a nucleic acid.

7. The system of claim 6, wherein the nucleic acid is a regulatory nucleic acid.

8. The system of claim 7, wherein the regulatory nucleic acid is siRNA, shRNA, or miRNA.

9. The system of claim 5, wherein the cell is an endothelial cell.

10. The system of claim 9, wherein the endothelial cell is a vascular endothelium cell.

11. The system of claim 1, wherein the implantable device is a stent.

12. The system of claim 1, wherein a surface of the particle is modified to prolong bioavailability.

13. A method for magnetically targeting a therapeutic particle to an implanted device, comprising the steps of:

(a) administering to a subject a particle comprising at least one therapeutic agent and a first magnetic or magnetizable material;

(b) generating a uniform magnetic field capable of magnetizing magnetizable materials, wherein the uniform magnetic field generates a magnetic field gradient proximal to the implanted device comprising a second magnetic or magnetizable material, wherein the gradient targets the particle to the implanted device; and

(c) removing particles not delivered to the implanted device.

14. The method of claim 13, further comprising the step of removing spent particles.

15. The method of claim 13, wherein the therapeutic agent is a pharmaceutical, biomolecule, or cell.

16. The method of claim 15, wherein the biomolecule is a nucleic acid.

17. The method of claim 16, wherein the nucleic acid is a regulatory nucleic acid.

18. The method of claim 17, wherein the regulatory nucleic acid is siRNA, shRNA, or miRNA.

19. The method of claim 15, wherein the cell is an endothelial cell.

20. The method of claim 19, wherein the endothelial cell is a vascular endothelium cell.

21. The method of claim 13, wherein the implanted device is a stent.

22. The method of claim 13, wherein the step of removing particles not delivered to the implanted device comprises reversibly connecting a third magnetic or magnetizable material to the subject and generating a second magnetic field gradient proximal to the third magnetic or magnetizable material, wherein the second magnetic field gradient targets the particles to the third magnetic or magnetizable material.

23. The method of claim 14, wherein the step of removing spent particles comprises reversibly connecting a third magnetic or magnetizable material to the subject and generating a second magnetic field gradient proximal to the third magnetic or magnetizable material, wherein the second magnetic field gradient targets the spent particles to the third magnetic or magnetizable material.

24. The method of claim 22, wherein the third magnetic or magnetizable material is reversibly connected to at least one blood vessel of the subject.

25. The method of claim 23, wherein the third magnetic or magnetizable material is reversibly connected to at least one blood vessel of the subject.

26. The method of claim 13, wherein the step of removing particles not delivered to the implanted device comprises removing the blood of the subject, contacting the blood with a third magnetic or magnetizable material, generating a second magnetic field gradient proximal to the third magnetic or magnetizable material, wherein the second magnetic field gradient targets particles to the third magnetic or magnetizable material, and returning the blood to the subject, wherein the returned blood is substantially free of particles.

27. The method of claim 14, wherein the step of removing spent particles comprises removing the blood of the subject, contacting the blood with a third magnetic or magnetizable material, generating a second magnetic field gradient proximal to the third magnetic or magnetizable material, wherein the second magnetic field gradient targets the spent particles to the third magnetic or magnetizable material, and returning the blood to the subject, wherein the returned blood is substantially free of the spent particles.

28. A method for preparing nanoparticles comprising the steps of:

(a) providing a first aqueous solution comprising a water soluble salt of a mono-carboxylic fatty acid or a lipid mono-phosphate, a stabilizer, and at least one therapeutic agent; and

(b) adding to the first aqueous solution a second aqueous solution comprising a polyvalent biocompatible cation.

29. The method of claim 28, wherein the first aqueous solution further comprises magnetic nanocrystals.

30. The method of claim 29, further comprising forming the magnetic nanocrystals in the first aqueous solution.

31. The method of claim 28, wherein the water soluble salt of the fatty acid or the lipid mono-phosphate is sodium oleate.

32. The method of claim 28, wherein the stabilizer is albumin.

33. The method of claim 28, wherein the polyvalent biocompatible cation is calcium ion.

34. The method of claim 28, wherein the second aqueous solution further comprises at least one cationic polypeptide.

35. The method of claim 34, wherein the cationic peptide is poly-L-arginine.

36. The method of claim 28, wherein the at least one therapeutic agent is taxol or all-trans retinoic acid.