RNA nanoparticles for brain tumor treatment

Patent metadata

Field	Value
Publication number	US-10584144-B2
Application number	US-201615554360-A
Country	US
Kind code	B2
Filing date	Mar 9, 2016
Priority date	Mar 9, 2015
Publication date	Mar 10, 2020
Grant date	Mar 10, 2020

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. 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 the 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. The molecule of claim 1 further comprising at least one bioactive agent coupled to the RNA junction motif.

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

4. The molecule of claim 3 , wherein the modification comprises 2′ Fluoro, 2′ Amine, 2′ O-Methyl, or a combination thereof.

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

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

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

8. The molecule of claim 5 , 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.

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

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

11. The molecule of claim 10 , wherein the ligand binds to a folate receptor, an EGFR, a transferrin receptor, an RGD, or a combination thereof.

12. The molecule of claim 10 , wherein the ligand comprises an aptamer.

13. The molecule of claim 11 , wherein the aptamer binds to EGFR, PDGFR, folate receptor, or a combination thereof.

14. The molecule of claim 1 , wherein the targeting module comprises a folate.

15. The molecule of claim 2 , 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.

16. The molecule of claim 2 , wherein the bioactive agent is directed to a brain tumor marker.

17. The molecule of claim 15 , wherein the microRNA sequence is at least 6 nucleotide in length.

18. The molecule of claim 15 , wherein the bioactive agent is an anti-miRNA molecule for a miRNA comprising miR-9, miR-10b, miR-21, miR-17, or miR-26.

19. The molecule of claim 15 , 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.

20. The molecule of claim 18 , wherein the anti-miRNA comprises an anti-miRNA locked nucleic acid (LNA) molecule.

21. The molecule of claim 20 , wherein the anti-miRNA LNA molecule comprises sequence 5′-GATAAGCT-3′, 5′-AGCACTTT-3′, or 5′-ATTTGCAC-3′.

22. The molecule of claim 15 , wherein the 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.

23. The molecule of claim 15 , wherein the siRNA binds to a mRNA molecule that encodes RAS, cMET, HER2, MDM2, PIK3CA, AKT, CDK4, or a combination thereof.

24. A nucleic acid composition, comprising a therapeutically effective amount of the RNA nano structure of claim 1 .

25. The composition of claim 24 , further comprising a pharmaceutically acceptable carrier.

26. The artificial RNA nanostructure of claim 1 , wherein the RNA nanostructure comprises a nanoparticle delivery system.

27. The nanoparticle delivery system of claim 26 , further comprising a pharmaceutically acceptable carrier.

Assignees

• Univ Kentucky Res Found

Inventors

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

Classifications

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C12N2310/52

  branched · CPC title

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · 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