Methods for treating subjects suffering from acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles
A nanoparticle delivery system designed for sustained delivery of microRNA-150 (miR-150) to FLT3-overexpressing acute myeloid leukemia (AML) cells, the delivery system comprising poly(amidoamine) (PAMAM) dendrimers complexed with miR-150, wherein at least one dendrimer is surface-functionalized with a ligand specific for FLT3 receptor, and methods for treating AML characterized by FLT3-overexpression are provided.
1. A method of treating acute myeloid leukemia (AML) in a patient in need thereof, the method comprising: administering to the patient an FLT3-guided dendrimeric nanoparticle complexed with miR-150, wherein the FLT3-guided dendrimeric nanoparticle comprises a PAMAM dendrimer that is surface-functionalized with a ligand specific for FLT3 receptor, said ligand consists of a natural and/or synthetic FLT3L peptide having at least 90% sequence homology to SEQ ID NO: 1.
2. The method according to claim 1 , wherein the AML is characterized by overexpression of FLT3.
3. The method according to claim 1 , wherein the ligand consists of a synthetic FLT3L peptide having an amino acid sequence as set forth in SEQ ID NO: 1.
4. The method according to claim 1 , wherein the PAMAM dendrimer comprises a G2, G3, G4, G5, G6, G7, or G8-dendrimer.
5. The method according to claim 4 , wherein the PAMAM dendrimer comprises a G7-dendrimer.
6. The method according to claim 1 , wherein the miR-150 comprises a stability modification.
7. The method according to claim 6 , wherein the stability modification of miR-150 comprises 2′-O methylation.
8. The method according to claim 1 , wherein the complexed nanoparticle is G7-Flt3L-(2′OMe)miR-150.
9. The method according to claim 1 , wherein administering comprises systemic administration.
10. The method according to claim 9 , wherein systemic administration comprises intravenous administration.
11. The method according to claim 1 , further comprising administering at least one bromodomain and extra terminal motif (BET) protein inhibitor.
12. The method according to claim 11 , wherein the BET inhibitor targets both BD1 and BD2.
13. The method according to claim 11 , wherein the BET inhibitor is selected from the group consisting of JQ1, I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-201, CPI-0610, and combinations thereof.
14. The method according to claim 13 , wherein the BET inhibitor comprises JQ1.
15. The method according to claim 11 , wherein the FLT3-guided dendrimer nanoparticle complexed with miR-150 is administered before the BET inhibitor.
16. The method according to claim 11 , wherein the FLT3-guided dendrimer nanoparticle complexed with miR-150 is administered after the BET inhibitor.