Eradication of Acute Myeloid Leukemia with FLT3 Ligand-Targeted miR-150 Nanoparticles.
Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancy. Overexpression and/or mutations of FLT3 have been shown to occur in the majority of cases of AML. Our analysis of a large-scale AML patient cohort (N = 562) indicates that FLT3 is particularly highly expressed in some subtypes of AML, such as AML with t(11q23)/MLL-rearrangements or FLT3-ITD. Such AML subtypes are known to be associated with unfavorable prognosis. To treat FLT3-overexpressing AML, we developed a novel targeted nanoparticle system: FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) nanosized dendriplex encapsulating miR-150, a pivotal tumor suppressor and negative regulator of FLT3 We show that the FLT3L-guided miR-150 nanoparticles selectively and efficiently target FLT3-overexpressing AML cells and significantly inhibit viability/growth and promote apoptosis of the AML cells. Our proof-of-concept animal model studies demonstrate that the FLT3L-guided miR-150 nanoparticles tend to concentrate in bone marrow, and significantly inhibit progression of FLT3-overexpressing AML in vivo, while exhibiting no obvious side effects on normal hematopoiesis. Collectively, we have developed a novel targeted therapeutic strategy, using FLT3L-guided miR-150-based nanoparticles, to treat FLT3-overexpressing AML with high efficacy and minimal side effects. Cancer Res; 76(15); 4470-80. ©2016 AACR.
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. chen3jj@uc.edu jiangx4@uc.edu sphong@uic.edu.
Xi
X
Jiang
Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois.
Jason
J
Bugno
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Hematology, The First Affiliated Hospital and Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Chao
C
Hu
Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois.
Yang
Y
Yang
Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
Tobias
T
Herold
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Jun
J
Qi
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Ping
P
Chen
Department of Pathology, University of Chicago, Chicago, Illinois.
Sandeep
S
Gurbuxani
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Stephen
S
Arnovitz
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio.
Jennifer
J
Strong
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio.
Kyle
K
Ferchen
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Bryan
B
Ulrich
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Hengyou
H
Weng
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Hematology, The First Affiliated Hospital and Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Yungui
Y
Wang
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Hao
H
Huang
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Shenglai
S
Li
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Mary Beth
MB
Neilly
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Richard A
RA
Larson
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Michelle M
MM
Le Beau
Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
Stefan K
SK
Bohlander
Department of Hematology, The First Affiliated Hospital and Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
Jie
J
Jin
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Zejuan
Z
Li
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
James E
JE
Bradner
Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois. Division of Integrated Science & Engineering, Underwood International College, Yonsei University, Incheon, Korea. chen3jj@uc.edu jiangx4@uc.edu sphong@uic.edu.
Seungpyo
S
Hong
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. chen3jj@uc.edu jiangx4@uc.edu sphong@uic.edu.
Jianjun
J
Chen
D000818:Animals; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D053758:Nanoparticles
D008565:Membrane Proteins; D035683:MicroRNAs; C533097:MIR150, human; C084881:flt3 ligand protein