Use of polymeric CXCR4 inhibitors as siRNA delivery vehicles for the treatment of acute myeloid leukemia.
Animals
Antineoplastic Agents
/ administration & dosage
Benzylamines
/ administration & dosage
Cell Line, Tumor
Cholesterol
/ chemistry
Core Binding Factor Alpha 2 Subunit
/ antagonists & inhibitors
Cyclams
/ administration & dosage
Disease Models, Animal
Drug Carriers
/ chemistry
Female
Gene Knock-In Techniques
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Male
Mice
Mice, Transgenic
Nanoparticles
/ chemistry
Oncogene Proteins, Fusion
/ genetics
Polyelectrolytes
/ chemistry
RNA, Small Interfering
/ administration & dosage
Receptors, CXCR4
/ antagonists & inhibitors
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
07
02
2019
accepted:
13
04
2019
revised:
11
04
2019
pubmed:
28
4
2019
medline:
11
5
2021
entrez:
28
4
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31028289
doi: 10.1038/s41417-019-0095-9
pii: 10.1038/s41417-019-0095-9
doi:
Substances chimiques
Antineoplastic Agents
0
Benzylamines
0
CBFbeta-MYH11 fusion protein
0
CXCR4 protein, human
0
CXCR4 protein, mouse
0
Core Binding Factor Alpha 2 Subunit
0
Cyclams
0
Drug Carriers
0
Oncogene Proteins, Fusion
0
Polyelectrolytes
0
RNA, Small Interfering
0
RUNX1 protein, human
0
Receptors, CXCR4
0
Runx1 protein, mouse
0
polycations
0
Cholesterol
97C5T2UQ7J
plerixafor
S915P5499N
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
45-55Références
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