RNA nanoparticles for brain tumor treatment

Patent metadata

Field	Value
Publication number	US-11325939-B2
Application number	US-202016813087-A
Country	US
Kind code	B2
Filing date	Mar 9, 2020
Priority date	Mar 9, 2015
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

The presently-disclosed subject matter relates to an artificial RNA nanostructure molecule and method to treat brain tumor in a subject. More particularly, the presently disclosed subject matter relates to a RNA nanostructure containing a multiple branched RNA nanoparticle, a brain tumor targeting module, and an effective amount of a therapeutic agent. Further, the presently disclosed subject matter relates to a method of using the RNA nanostructure composition to treat brain tumor in a subject having or at risk of having brain tumor.

First claim

What is claimed is:

1. A method of treating a brain tumor in a subject having or at risk of developing a brain tumor, the method comprising administering to the subject a therapeutically effective amount of a composition comprising an artificial RNA nanostructure molecule, wherein the molecule comprises a multiple branched RNA junction motif comprising at least one RNA oligonucleotide, and a brain tumor targeting module, wherein the module is coupled to an RNA junction motif, wherein the multiple branched RNA comprises a nucleotide sequence 5′-UUG CCA UGU GUA UGU GGG AUC CCG CGG CCA UGG CGG CCG GGA G-3′ (SEQ ID NO: 6) or 5′-GATAAGCT CTC CCG GCC GCC ATG GCC GCG GGA T-3′ (SEQ ID NO: 7).

2. A method of preventing brain tumor recurrence in a subject having or at risk of having brain tumor recurrence, the method comprising administering to the subject a therapeutically effective amount of a composition comprising an artificial RNA nanostructure molecule, wherein the molecule comprises a multiple branched RNA junction motif comprising at least one RNA oligonucleotide, and a brain tumor targeting module, wherein the module is coupled to an RNA junction motif wherein the multiple branched RNA comprises a nucleotide sequence 5′-UUG CCA UGU GUA UGU GGG AUC CCG CGG CCA UGG CGG CCG GGA G-3′ (SEQ ID NO: 6) or 5′-GATAAGCT CTC CCG GCC GCC ATG GCC GCG GGA T-3′ (SEQ ID NO: 7).

3. The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.

4. The method of claim 1 , wherein the subject is a mammal or a non-mammal vertebrate.

5. The method of claim 1 , wherein the subject is a human.

6. The method of claim 1 , wherein the brain tumor is glioblastoma.

7. The method of claim 1 , wherein the molecule further comprises at least one bioactive agent coupled to the RNA junction motif.

8. The method of claim 1 , wherein the RNA oligonucleotide comprises at least one chemical modification at the 2′ position.

9. The method of claim 8 , wherein the modification comprises 2′ Fluoro, 2′ Amine, 2′ O-Methyl, or a combination thereof.

10. The method of claim 1 , wherein the motif is a three-branched RNA junction motif.

11. The method of claim 1 , wherein the diameter of the molecule is at least about 40 nm or less.

12. The method of claim 1 , wherein the molecule has a zeta potential ranging from about −50 m V to about 50 m V.

13. The method of claim 10 , wherein a branch of the three-branched RNA junction motif comprises an a3WJ RNA module (SEQ ID NO: 1); a b3WJ RNA module (SEQ ID NO: 2); a c3WJ RNA module (SEQ ID NO: 3); or a combination thereof.

14. The method of claim 1 , wherein RNA oligonucleotides comprises at least 6 nucleotides in length.

15. The method of claim 1 , wherein the brain tumor targeting module comprises a ligand that binds to at least one brain tumor cell surface marker.

16. The method of claim 15 , wherein the ligand binds to a folate receptor, an EGFR, a transferrin receptor, an RGD, or a combination thereof.

17. The method of claim 15 , wherein the ligand comprises an aptamer.

18. The method of claim 17 , wherein the aptamer binds to EGFR, PDGFR, folate receptor, or a combination thereof.

19. The method of claim 1 , wherein the targeting module comprises a folate.

20. The method of claim 7 , wherein the bioactive agent comprises a drug, a therapeutic agent, a fluorescent dye, a chemical, an siRNA, an miRNA, an anti-miRNA, a ribozyme RNA, an antisense RNA or a combination thereof.

21. The method of claim 7 , wherein the bioactive agent is directed to a brain tumor marker.

22. The method of claim 20 , the microRNA sequence is at least 6 nucleotide in length.

23. The method of claim 20 , wherein the bioactive agent is an anti-miRNA molecule for a miRNA comprising miR-9, miR-10b, miR-21, miR-17, or miR-26.

24. The method of claim 20 , wherein the bioactive agent is a miRNA molecule for a miRNA comprising let-7a, miR-10b, miR-25, miR-34a, miR-124, miR-145, or miR-181b.

25. The method of claim 23 , wherein the anti-miRNA comprises an anti-miRNA locked nucleic acid (LNA) molecule.

26. The method of claim 23 , wherein the anti-miRNA LNA molecule comprises sequence 5′-GATAAGCT-3′, 5′-AGCACTTT-3′, or 5′-ATTTGCAC-3′.

27. The method of claim 20 , wherein the siRNA binds to an mRNA molecule encodes a protein comprising VEGF, EGFR, POK, AKT, AGT, RAF, RAS, MAPK, ERK, MGMT, MMP-2, MMP-9, PDGF, PDGFR, IGF-1, HGF, mTOR, Cox-2 or TGFβ1.

28. The method of claim 20 , wherein the siRNA binds to a mRNA molecule that encodes RAS, cMET, HER2, MDM2, PIK3CA, AKT, CDK4, or a combination thereof.

Assignees

• Univ Kentucky Res Found

Inventors

• Guo Peixuan
• Croce Carlo M
• Lee Tae Jin
• Haque Farzin
• Li Hui

Classifications

• A61K47/6929

  the form being a nanoparticle, e.g. an immuno-nanoparticle · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C07H21/02 Primary

  with ribosyl as saccharide radical · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title