NOVEL NANO-PROBES FOR MOLECULAR IMAGING AND TARGETED THERAPY OF DISEASES

• US 20120107229A1
• Filed: 04/14/2010
• Published: 05/03/2012
• Est. Priority Date: 04/15/2009
• Status: Abandoned Application

• Current Assignee: The Board of Trustees of Michigan State University (Michigan State University)
• Original Assignee: The Board of Trustees of Michigan State University (Michigan State University)
• Inventors: Zhu, David, Huang, Xuefei, Abela, George
• Application Number:
  US13/264,823
• Publication Number:
  US 20120107229A1
• Time in Patent Office: Days
• US Class Current: 424/1.11
• 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 49/1833 having a (super)(para)magnetic core coated or functionalised with a small organic molecule oligomeric, polymeric, dendrimeric A61K49/1851
• CPC Class Codes: A61K 49/1845 the small organic molecule being a carbohydrate (monosaccharides, discacharides)
• CPC Class Codes: A61K 49/1848 the small organic molecule being a silane
• CPC Class Codes: A61K 49/1857 the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
• CPC Class Codes: A61K 49/1863 the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
• CPC Class Codes: A61K 49/1866 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
• CPC Class Codes: A61K 49/1875 coated or functionalised with an antibody
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present inventions relate to compositions and methods for imaging and treating atherosclerotic diseases, pathogen infections, and tumors by administering actively targeting magnetic nanoparticles. In particular, the present inventions provide new types of targeting ligands attached to magnetic nanoparticles for magnetic resonance imaging. The use of these targeted magnetic nanoparticles is contemplated as a means to treat atherosclerotic diseases, including but not limited to inhibiting and removing atherosclerotic plaques. Further, actively targeting magnetic nanoparticles are contemplated for use with multiple labels for use in nuclear medicine imaging, computed tomography (CT) techniques and other types of imaging for medical and research applications.

Claims

1. A composition, comprising a targeting ligand, wherein said targeting ligand targets a molecule associated with an atherosclerotic plaque, and a nanoparticle.

2. The composition of claim 1, wherein said targeting ligand is selected from the group consisting of hyaluronic acid, dextrin, cyclodextrin, mannose, a lectin siRNA, MMP-9 sensitive linker, MMP-9 substrate peptide SGPLF, statin, fibrin, NO prodrug, Simivastatin, selectins, CD44 and CD44 structural analogs.

3. The composition of claim 1, wherein said targeting ligand is selected from the group consisting of a hyaluronic acid (HA) molecule and a cyclodextrin (CD) dimer.

4. The composition of claim 1, wherein said molecule is a target analyte.

5. The composition of claim 4, wherein said target analyte is selected from the group consisting of CD44, Vascular Cell Adhesion Molecule-1, Inter-Cellular Adhesion Molecule-1, cholesterol, fibrin, MMP, and phosphatidyl serine.

6. The composition of claim 4, wherein said target analyte is selected from the group consisting of CD44 and cholesterol.

7. The composition of claim 1, further comprising a therapeutic agent.

8. The composition of claim 7, wherein said therapeutic agent is selected from the group consisting of a siRNA, an anti-proinflammatory agent, interleukins, growth factors, siRNA, MMP inhibitors, cholesterol binding molecules, cortisone steroids and a HA antiadhesive.

9. The composition of claim 7, wherein said therapeutic agent is selected from the group consisting of lovastatin, diazeniumdiolate, anti-TNF-α

siRNA, interferon (IFN)-γ

, a colony stimulating factors, and a MMP-9 sensitive linker.

10. The composition of claim 7, wherein said nanoparticle comprises a magnetic compound.

11. The composition of claim 10, wherein said magnetic compound is selected from the group consisting of Iron Oxide, Fe₃O₄, iron cobalt, gold and iron-platinum (FePt).

12. The composition of claim 11, wherein said nanoparticle further comprises a positron emission tomography (PET) label capable of providing a diagnostic computed tomography (CT) image, wherein said PET label is selected from the group consisting of PET tracer ⁶⁴Cu and 18F labeled 2-deoxy glucose (18FDG).

13. The composition of claim 1, wherein said nanoparticle further comprises a label capable of providing a nuclear magnetic resonance (NMR) image, wherein said compound is gadolinium.

14. The composition of claim 1, wherein said nanoparticle further comprises a label capable of providing a magnetic resonance spectroscopy (MRS) spectrum.

15. The composition of claim 1, wherein said nanoparticle has a diameter greater than 0 and less than or equal to 6 nm.

16. The composition of claim 1, wherein said nanoparticle further comprises a fluorohphore fluorescein isocyanate (FITC).

17. A method, comprising,

a) providing,

i) a composition, comprising a targeting ligand, wherein said targeting ligand targets a molecule associated with an atherosclerotic plaque, and a nanoparticle;

ii) a patient at risk for a cardiac event;

iii) an magnetic resonance imaging device; and

b) administering said composition to said patient for providing a diagnostic magnetic resonance image of an atherosclerotic plaque.

18. The method of claim 17, wherein said targeting ligand is selected from the group consisting of a hyaluronic acid (HA) molecule and a cyclodextrin (CD) dimer.

19. The method of claim 17, wherein said targeting ligand targets a target analyte.

20. The method of claim 18, wherein said hyaluronic acid (HA) molecule targets a plaque macrophage.

21. The method of claim 18, wherein said cyclodextrin (CD) dimer targets a cholesterol crystal.

22. The method of claim 17, wherein said nanoparticle further comprises a therapeutic agent for targeted drug delivery.

23. The method of claim 22, wherein said nanoparticle is capable of delivering the therapeutic agent to a plaque;

wherein said therapeutic agent is selected from the group consisting of a siRNA, a MMP-9 sensitive linker, MMP-9 substrate peptide SGPLF, a statin, lovastatin, fibrin, a nitrous oxide (NO) prodrug, Simivastatin, selectins, CD44 structural analogs, anti-proinflammatory agent, interleukin, growth factor, siRNA of TNF-alpha, MMP inhibitor, cholesterol binding molecule, cortisone steroid and a HA antiadhesive.

24. The method of claim 17, wherein said targeting ligand targets a physiological event selected from the group consisting of macrophage activation, cholesterol crystal formation, angiogenesis, and apoptosis.

25. The method of claim 17, wherein said patient has atherosclerosis.

26. The method of claim 17, wherein said atherosclerotic plaque is selected from the group consisting of a pre-plaque, wherein a pre-plaque is a damaged artery wall, a vulnerable plaque, and a growing plaque.

27. The method of claim 17, wherein said nanoparticle further comprises the capability of providing a medical image, wherein said image is provided by devices selected from the group consisting of magnetic resonance spectroscopy (MRS), nuclear magnetic resonance imaging (NMR), multimodal imaging, fluorescent, positron emission tomography (PET) and computed tomography (CT).

28. The method of claim 17, wherein said administering comprises injecting 50-60 nmol/kg of said nanoparticle.

29. The method of claim 17, wherein said nanoparticle comprises a magnetic compound.

30. The method of claim 29, wherein said magnetic compound is selected from the group consisting of Iron Oxide, Fe₃O₄, iron cobalt, gold and iron-platinum (FePt).

31. The method of claim 17, wherein said nanoparticle further comprises a positron emission tomography (PET) label capable of providing a diagnostic computed tomography (CT) image, wherein said PET label is selected from the group consisting of PET tracer ⁶⁴Cu and 18F labeled 2-deoxy glucose (18FDG).