Methods for treating acute myeloid leukemia and nanoparticle complexes of miR-22 utilized therein

Patent metadata

Field	Value
Publication number	US-10400242-B2
Application number	US-201715803190-A
Country	US
Kind code	B2
Filing date	Nov 3, 2017
Priority date	Nov 3, 2016
Publication date	Sep 3, 2019
Grant date	Sep 3, 2019

Abstract

Compositions and methods for treating acute myeloid leukemia (AML) based on upregulating expression of microRNA-22 (miR-22), and a nanoparticle delivery system that utilizes FLT3-functionalized polyamidoamine (PAMAM) dendromirs for targeted delivery of miR-22 and/or agents that upregulate expression of miR-22 to AML cells.

First claim

The invention claimed is:

1. A nanoparticle delivery system designed for sustained delivery of microRNA-22(miR-22) to acute myeloid leukemia (AML) cells, the nanoparticle delivery system comprising poly(amidoamine) (PAMAM) dendrimers complexed with miR-22, wherein at least one dendrimer is surface-functionalized with a ligand specific for FLT3 receptor.

2. The delivery system according to claim 1 , wherein the PAMAM dendrimers comprise between generation-2 and generation-8 dendrimers.

3. The delivery system according to claim 1 , wherein the PAMAM dendrimers comprise generation 7 (G7) dendrimers.

4. The delivery system according to claim 1 , wherein the ligand specific for FLT3 receptor comprises a natural or synthetic FLT3L peptide.

5. The delivery system according to claim 1 , wherein the ligand specific for FLT3 receptor comprises a synthetic FLT3L peptide having at least 90% sequence homology to SEQ ID NO: 3.

6. The delivery system according to claim 5 wherein the synthetic FLT3L peptide is Flt3L peptide comprising SEQ ID NO: 3.

7. The delivery system according to claim 1 , wherein the miR-22 is modified for stability.

8. The delivery system according to claim 7 , wherein the miR-22 stability modification comprises 2′-O methylation.

9. The nanoparticle delivery system according to claim 1 comprising G7-Flt3L-(2′OMe)miR-22.

10. A pharmaceutical composition formulated as an injectable composition comprising a nanoparticle delivery system according to claim 1 .

11. A method of treating a patient suffering from de novo acute myeloid leukemia (AML), the method comprising: administering to the patient a nanoparticle complex comprising poly(amidoamine) (PAMAM) dendrimers complexed with miR-22, wherein at least one dendrimer is surface-functionalized with a ligand specific for FLT3receptor.

12. The method according to claim 11 , wherein the nanoparticle complex comprises a G2, G3, G4, G6 or G8- polyamidoamine (PAMAM) dendrimer.

13. The method according to claim 12 , wherein the ligand specific for FLT3 receptor comprises a natural and/or synthetic FLT3L peptide.

14. The method according to claim 13 , wherein the ligand specific for FLT3 receptor comprises a synthetic FLT3L peptide having at least 90% sequence homology to SEQ ID NO: 3.

15. The method according to claim 14 , wherein the ligand specific for FLT3 receptor comprises Flt3L peptide consisting essentially of SEQ ID NO: 3.

16. The method according to claim 11 , wherein the miR-22 comprises at least one stability modification.

17. The method according to claim 16 , wherein the stability modification of miR-22comprises 2′-O methylation.

18. The method according to claim 11 , wherein the nanoparticle complex is G7-Flt3L-(2′OMe)miR-22.

19. The method according to claim 11 , wherein administering comprises systemic administration.

20. The method according to claim 19 , wherein systemic administration comprises intravenous administration.

21. The method according to claim 11 , further comprising administering at least one agent that directly or indirectly induces miR-22 expression.

22. The method according to claim 21 , wherein the at least one agent is selected from all-trans-retinoic acid (ATRA) and NSC-370284.

23. The method according to claim 22 , wherein the nanoparticle complex comprising miR-22 is administered before, after, or simultaneously with the at least one agent.

24. A method of treating a patient suffering from acute myeloid leukemia, the method comprising administering G7-Flt3L-(2′OMe)miR-22 to the patient.

Assignees

• Univ Cincinnati

Inventors

• Chen Jianjun
• Jiang Xi

Classifications

• C12N2320/31

  Combination therapy · 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

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title