Magnetic nanoparticle-samirna complex and method for preparing same

Patent metadata

Field	Value
Publication number	US-9649388-B2
Application number	US-201314372211-A
Country	US
Kind code	B2
Filing date	Jan 17, 2013
Priority date	Jan 18, 2012
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

Provided are a SAMiRNA-magnetic nanoparticle complex capable of effectively delivering a double-stranded oligo RNA and magnetic nanoparticles into a cell and a composition capable of simultaneously performing diagnosis and therapy of diseases such as cancer, and the like, containing the same. More specifically, provided is the SAMiRNA-magnetic nanoparticle complex consisting of double-stranded oligo RNA-polymer structures in which a hydrophilic material and a second hydrophobic material are bound to the double-stranded oligo RNA by a simple covalent bond or a linker-mediated covalent bond, and the magnetic nanoparticles in which a first hydrophobic material is bound onto a surface of the magnetic material, as a core.
The SAMiRNA-magnetic nanoparticle complex may have a homogeneous size by a hydrophobic interaction between the first hydrophobic material of the present invention and the second hydrophobic material of the double-stranded oligo RNA structure.
In addition, the hydrophilic material and the second hydrophobic material bound to the double-stranded oligo RNA structure may improve in vivo stability of the double-stranded oligo RNA, an additionally bound ligand may deliver the SAMiRNA-magnetic nanoparticle complex into a target cell even at a relative low concentration of dosage, and the magnetic materials of the magnetic nanoparticles may be used as an imaging agent for diagnosis.

First claim

The invention claimed is:

1. A SAMiRNA(s)-magnetic nanoparticle(s) complex comprising: magnetic nanoparticle(s) comprising first hydrophobic material coated on a surface of a magnetic material; and a structure comprising second hydrophobic material, double stranded oligo RNA and hydrophilic material wherein the structure is represented by the following Formula (1):
A-X—R—Y—B  Formula (1)

wherein: one of A and B is said hydrophilic material, the other one is said second hydrophobic material; X and Y are each independently a simple covalent bond or a linker-mediated covalent bond; and R is said double-stranded oligo RNA, and
wherein the magnetic nanoparticle is positioned in a core by hydrophobic interaction between the first hydrophobic material and the second hydrophobic material, the structure is positioned in a shell, and the hydrophilic material of the structure is bound to the outermost side of the double-stranded oligo RNA.

2. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the first hydrophobic material and the second hydrophobic material are the same or different.

3. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein a mass ratio of the magnetic nanoparticle to double stranded oligo RNA structure is from 0.01:1 to 100:1.

4. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the SAMiRNA-magnetic nanoparticle complex has a diameter of 50 to 300 nm.

5. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the SAMiRNA-magnetic nanoparticle complex has polydispersity index (PDI) of 0.01 to 0.4.

6. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the magnetic material has a diameter of 1 nm to 200 nm.

7. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the magnetic material is a magnetic metal or a magnetic metal oxide.

8. The SAMiRNA-magnetic nanoparticle complex according to claim 7 , wherein the magnetic metal is one or more metal(s) selected from the group consisting of Fe, Ni, Co, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Cu, Ag, Au, Zn, Cd, Hg, Al, Ga, In, Tl, Ca, Sr, Ba, Ra, Pt, and Pd.

9. The SAMiRNA-magnetic nanoparticle complex according to claim 7 , wherein the magnetic metal oxide is oxide of one or more metal(s) selected from the group consisting of Fe, Ni, Co, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Cu, Ag, Au, Zn, Cd, Hg, Al, Ga, In, Tl, Ca, Sr, Ba, Ra, Pt and Pd, or oxide of alloys thereof.

10. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the first hydrophobic material of the magnetic nanoparticle is one or more selected from the group consisting of C6 to C25 aromatic compound, C6 to C25 ether, C6 to C25 aliphatic hydrocarbon and C6 to C25 amine.

11. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the double-stranded oligo RNA structure has a structure represented by the following Formula (1′):

Wherein A, X, Y, and B have the meanings and linkages specified in claim 1 , S is a sense strand of the double-stranded oligo RNA, and AS is an antisense strand of the double-stranded oligo RNA.

12. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the double-stranded oligo RNA structure has a structure represented by the following Formula (2):

Wherein A, X, Y, and B have the meanings and linkages specified in claim 1 , S is a sense strand of the double-stranded oligo RNA and AS is an antisense strand of the double-stranded oligo RNA.

13. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the double-stranded oligo RNA has 19 to 31 nucleotides.

14. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the covalent bond is a non-degradable bond or a degradable bond.

15. The SAMiRNA-magnetic nanoparticle complex according to claim 14 , wherein the non-degradable bond is an amide bond or a phosphate bond.

16. The SAMiRNA-magnetic nanoparticle complex according to claim 14 , wherein the degradable bond is one or more selected from the group consisting of a disulfide bond, an acid degradable bond, an ester bond, an anhydride bond, a biodegradable bond and an enzymatically degradable bond.

17. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the second hydrophobic material has a molecular weight of 100 to 2,000.

18. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the second hydrophobic material is one or more selected from the group consisting of a steroid derivative, a glyceride derivative, glycerol ether, polypropylene glycol, unsaturated or saturated C12 to C50 hydrocarbons, diacylphosphatidylcholine, fatty acid, phospholipid and lipopolyamine.

19. The SAMiRNA-magnetic nanoparticle complex according to claim 18 , wherein the steroid derivative is one or more selected from the group consisting of cholesterol, cholestanol, cholic acid, cholesteryl formate, cholestanyl formate, and cholestanyl amine.

20. The SAMiRNA-magnetic nanoparticle complex according to claim 18 , wherein the glyceride derivative is one or more selected from the group consisting of mono-, diand tri-glyceride.

21. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the hydrophilic material is a non-ionic polymer having a molecular weight of 1,000 to 10,000.

22. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein the hydrophilic material is one or more selected from the group consisting of polyethylene glycol (PEG), polyvinylpyrolidone and polyoxazoline.

23. The SAMiRNA-magnetic nanoparticle complex according to claim 1 , wherein said structure comprises a ligand bound thereto.

24. The SAMiRNA-magnetic nanoparticle complex according to claim 23 , wherein the ligand is one or more, which is bound in a target-specific way to effect receptormediated endocytosis (RME), selected from the group consisting of target specific antibody, aptamer, peptide, and a receptor-specific chemical material.

25. The SAMiRNA-magnetic nanoparticle complex according to claim 23 , wherein the receptor-specific chemical material is one or more selected from the group consisting of folate, N-acetyl galactosamine (NAG) and mannose.

26. A method of preparing SAMiRNA(s)-magnetic nanoparticle(s) complex according to claim 1 , said method comprising:
(1) preparing a double-stranded oligo RNA structure containing a hydrophilic material and a second hydrophobic material bound thereto;
(2) preparing a magnetic nanoparticle comprising a first hydrophobic material coated on a surface of the magnetic material; and
(3) mixing a SAMiRNA comprising the double-stranded oligo RNA structure and the magnetic nanoparticle containing the first hydrophobic material coated on the surface of the magnetic material.

27. The method according to claim 26 , wherein the method further comprises a step of binding a ligand to the hydrophilic material of the double-stranded oligo RNA structure.

28. A pharmaceutical composition comprising a SAMiRNA magnetic nanoparticle complex according to claim 1 .

29. A composition for diagnosis

Assignees

• Bioneer Corp

Inventors

• Chae Jeiwook
• Chung Hyunjin
• Lee Boreum
• Park Han Oh

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/7105

  Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K9/14 Primary

  Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)} · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title