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

Cancer Gene Therapy volume 27, pages 45–55 (2020)Cite this article

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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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Acknowledgements

We thank UNMC Flow Cytometry Research and the UNMC Center for Comparative Medicine. This work was supported by the state of Nebraska through LB606 and the Nebraska Pediatric Cancer Research Group.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Yiqian Wang, Jacob Williams, Lisa Richter, Michelle Becker & R. Katherine Hyde

  2. Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA

    Ying Xie, Yu Hang & David Oupický

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    Catalina Amador

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  1. Yiqian Wang
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Contributions

Y.W., Y.X., D.O., and R.K.H. conceived of and designed the study; Y.W., Y.X., J.W., Y.H., L.R., and M.B. performed experiments; C.A. performed histological evaluations. Y.W., Y.X., D.O., and R.K.H. wrote the manuscript.

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Correspondence to R. Katherine Hyde.

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Wang, Y., Xie, Y., Williams, J. et al. Use of polymeric CXCR4 inhibitors as siRNA delivery vehicles for the treatment of acute myeloid leukemia. Cancer Gene Ther 27, 45–55 (2020). https://doi.org/10.1038/s41417-019-0095-9

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