Uniform field magnetization and targeting of therapeutic formulations

• US 9,028,829 B2
• Filed: 12/15/2009
• Issued: 05/12/2015
• Est. Priority Date: 02/20/2004
• Status: Expired due to Fees

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Children's Hospital of Philadelphia (Children's Hospital of Philadelphia Foundation)
• Inventors: Levy, Robert J., Chorny, Michael, Muzykantov, Vladimir, Hood, Elizabeth
• Primary Examiner(s): Matthews, Christine H
• Assistant Examiner(s): LANNU, JOSHUA DARYL DEANON
• Application Number:
  US12/653,465
• Publication Number:
  US 20100260780A1
• Time in Patent Office: 1,974 Days
• Field of Search: 128/897, 128/898, 128/899, 60/9, 60/12, 424/489, 424/499
• US Class Current: 424/172.1
• 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 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 47/6455 Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6921 the form being a particulate, a powder, an adsorbate, a bead or a sphere
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• 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: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/60 characterised by a special physical form
• CPC Class Codes: A61L 2300/624 Nanocapsules
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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

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. Therapeutic particles can comprise antioxidant enzymes, and can be targeted to cells to protect the cells from oxidative damage.

Claims

1. A therapeutic particle comprising:

a magnetic or magnetizable material,

a colloidal stabilizer,

a therapeutic protein, and

a precipitated complex formed between one or more anionic lipids and one or more biocompatible polyvalent cations,

wherein said one or more biocompatible polyvalent cations in said precipitated complex are different from any cations in said magnetic or magnetizable material,

wherein said therapeutic particle is a nanoparticle,

wherein the therapeutic particle is made by a process comprising forming the precipitated complex in the presence of the magnetic or magnetizable material, the colloidal stabilizer and the therapeutic protein.

2. The therapeutic particle of claim 1, wherein the magnetic or magnetizable material is a superparamagnetic material.

3. The therapeutic particle of claim 1, wherein the one or more anionic lipids comprise oleic acid or a salt thereof.

4. The therapeutic particle of claim 1, wherein the therapeutic protein is an antioxidant enzyme.

5. The therapeutic particle of claim 4, wherein the antioxidant enzyme is catalase, superoxide dismutase, or glutathione peroxidase.

6. The therapeutic particle of claim 1, wherein the colloidal stabilizer is biotinylated.

7. The therapeutic particle of claim 1, further comprising an antibody.

8. The therapeutic particle of claim 7, wherein the antibody is joined to the colloidal stabilizer.

9. The therapeutic particle of claim 7, wherein the antibody is capable of specifically binding to an antigen on the surface of an endothelial cell.

10. The therapeutic particle of claim 1, further comprising paclitaxel.

11. The therapeutic particle of claim 1, wherein the one or more anionic lipids comprise a fatty acid or salt thereof.

12. The therapeutic particle of claim 1, wherein the one or more biocompatible polyvalent cations comprise Ca⁺⁺.

13. The therapeutic particle of claim 1, comprising calcium cations complexed with oleate anions.

14. The therapeutic particle of claim 1, wherein the precipitated complex is formed in the absence of organic solvents.

15. A method for protecting a cell from oxidative damage, comprising contacting the cell with the therapeutic particle according to claim 1, wherein the therapeutic protein comprises at least one antioxidant enzyme, and generating a uniform magnetic field capable of magnetizing the magnetic or magnetizable material proximal to the cell for a period of time sufficient to permit the cell to internalize the particle, wherein the uniform magnetic field is produced by a magnetic field generator comprising first and second magnets configured and operable to generate the uniform magnetic field.

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

17. The method of claim 16, wherein the endothelial cell is a vascular endothelium cell.

18. The method of claim 15, wherein the antioxidant enzyme is catalase, superoxide dismutase, or glutathione peroxidase.

19. The method of claim 15, wherein the particle further comprises an antibody capable of specifically binding to an antigen on the surface of the cell.

20. The method of claim 15, wherein the cell is in the body of a mammal.

25. The method of claim 21, wherein each of the plurality of particles is the particle of claim 1.

21. A method for magnetically targeting a protein to an intracorporeal device, comprising the steps of:

(a) administering to a subject having an intracorporeal device a plurality of particles comprising a first magnetic or magnetizable material and the protein; and

(b) generating a uniform magnetic field capable of magnetizing magnetizable materials, the uniform magnetic field generating a magnetic field gradient proximal to the intracorporeal device, the intracorporeal device comprising a second magnetic or magnetizable material, wherein the gradient targets one or more of the plurality of particles to the intracorporeal device;

wherein the uniform magnetic field is produced by a magnetic field generator comprising first and second magnets configured and operable to generate the uniform magnetic field across the intracorporeal device.

22. The method of claim 21, further comprising the step of removing spent particles from the subject.

23. The method of claim 21, wherein the protein is an antioxidant enzyme.

24. The method of claim 23, wherein the antioxidant enzyme is catalase, superoxide dismutase, or glutathione peroxidase.

26. The method of claim 21, wherein the intracorporeal device is a stent.

27. The method of claim 26, wherein the stent is formed of 304 stainless steel.

28. The method of claim 21, wherein the step of generating a uniform magnetic field comprises using a permanent magnet to generate the uniform magnetic field.

29. The method of claim 21, wherein the first magnetic or magnetizable material comprises a superparamagnetic material.

30. The method of claim 21 further comprising the steps of:

(a) removing the uniform magnetic field and magnetic field gradient;

(b) administering to the subject another plurality of particles comprising the first magnetic or magnetizable material and the protein;

(c) repeating the step of generating a uniform magnetic field to generate a magnetic field gradient proximal to the intracorporeal device to target one or more of said another plurality of particles to the intracorporeal device and deliver an additional quantity of the protein to the device.

31. The method of claim 21 further comprising a step of administering to the subject a plurality of particles comprising the first magnetic or magnetizable material and paclitaxel.

32. The method of claim 21 wherein the plurality of particles comprising the first magnetic or magnetizable material further comprises paclitaxel.

33. The method of claim 21, wherein some of the plurality of particles administered to the subject are not delivered to the intracorporeal device and are removed from the subject.