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Cancer Res. 2016 Aug 1;76(15):4470-80. doi: 10.1158/0008-5472.CAN-15-2949. Epub 2016 Jun 8.

Eradication of Acute Myeloid Leukemia with FLT3 Ligand-Targeted miR-150 Nanoparticles.

Author information

1
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.
2
Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois.
3
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.
4
Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
6
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
7
Department of Pathology, University of Chicago, Chicago, Illinois.
8
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio.
9
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
10
Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
11
Department of Hematology, The First Affiliated Hospital and Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China.
12
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.

Abstract

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.

PMID:
27280396
PMCID:
PMC4970973
DOI:
10.1158/0008-5472.CAN-15-2949
[Indexed for MEDLINE]
Free PMC Article

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