Use of polymeric CXCR4 inhibitors as siRNA delivery vehicles for the treatment of acute myeloid leukemia

Yiqian Wang, Ying Xie, Jacob Williams, Yu Hang, Lisa Richter, Michelle Becker, Catalina Amador, David Oupický, R. Katherine Hyde

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalCancer Gene Therapy
DOIs
StatePublished - Jan 1 2019

Fingerprint

CXCR4 Receptors
Acute Myeloid Leukemia
Small Interfering RNA
Leukemia
Oncogenes
Therapeutics
Recurrence
Nanoparticles
Transcription Factors
Drug Therapy
Survival
Genes
JM 3100

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Cite this

Use of polymeric CXCR4 inhibitors as siRNA delivery vehicles for the treatment of acute myeloid leukemia. / Wang, Yiqian; Xie, Ying; Williams, Jacob; Hang, Yu; Richter, Lisa; Becker, Michelle; Amador, Catalina; Oupický, David; Hyde, R. Katherine.

In: Cancer Gene Therapy, 01.01.2019.

Research output: Contribution to journalArticle

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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.",
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AU - Xie, Ying

AU - Williams, Jacob

AU - Hang, Yu

AU - Richter, Lisa

AU - Becker, Michelle

AU - Amador, Catalina

AU - Oupický, David

AU - Hyde, R. Katherine

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