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Use of polymeric CXCR4 inhibitors as siRNA delivery vehicles for the treatment of acute myeloid leukemia
- Source :
- Cancer gene therapy. 27(1-2)
- Publication Year :
- 2019
-
Abstract
- Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and is associated with poor long-term survival often owing to relapse. Current treatments for AML are associated with considerable toxicity and are frequently not effective after relapse. Thus, it is important to develop novel therapeutic strategies. Short interfering RNA (siRNA)-based therapeutics targeting key oncogenes have been proposed as treatments for AML. We recently developed novel siRNA delivery polycations (PCX) based on AMD3100 (plerixafor), an FDA-approved inhibitor of the CXC chemokine receptor 4 (CXCR4). Inhibitors of CXCR4 have been shown to sensitize leukemia cells to chemotherapy. Therefore, PCX has the potential to target leukemia cells via two mechanisms: inhibition of CXCR4 and delivery of siRNAs against critical genes. In this report, we show that PCX exerts a cytotoxic effect on leukemia cells more effectively than other CXCR4 inhibitors, including AMD3100. In addition, we show that PCX can deliver siRNAs against the transcription factor RUNX1 to mouse and human leukemia cells. Overall, our study provides the first evidence that dual-function PCX/siRNA nanoparticles can simultaneously inhibit CXCR4 and deliver siRNAs, targeting key oncogenes in leukemia cells and that PCX/siRNA has clinical potential for the treatment of AML.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Small interfering RNA
Benzylamines
Receptors, CXCR4
Myeloid
Oncogene Proteins, Fusion
Antineoplastic Agents
Mice, Transgenic
Cyclams
CXCR4
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
hemic and lymphatic diseases
Cell Line, Tumor
medicine
Animals
Humans
CXC chemokine receptors
Gene Knock-In Techniques
RNA, Small Interfering
Molecular Biology
Acute leukemia
Drug Carriers
business.industry
Myeloid leukemia
medicine.disease
Polyelectrolytes
Leukemia
Disease Models, Animal
Leukemia, Myeloid, Acute
030104 developmental biology
medicine.anatomical_structure
Cholesterol
RUNX1
chemistry
030220 oncology & carcinogenesis
Core Binding Factor Alpha 2 Subunit
Cancer research
Molecular Medicine
Nanoparticles
Female
business
Subjects
Details
- ISSN :
- 14765500
- Volume :
- 27
- Issue :
- 1-2
- Database :
- OpenAIRE
- Journal :
- Cancer gene therapy
- Accession number :
- edsair.doi.dedup.....61104315c4f4d7848d2866af3501f84d