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In vivo targeting of leukemia stem cells by directing parthenolide-loaded nanoparticles to the bone marrow niche

Leukemia volume 30, pages 1582–1586 (2016)Cite this article

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Acute myelogenous leukemia (AML) is a deadly disease characterized by high relapse rates, despite the ability of patients to initially enter complete remission.1 Although new therapeutics are urgently needed, standard chemotherapy for AML has remained largely unchanged during the past four decades and the therapeutic outcomes remain dismal. The relapse in AML is thought to be driven by leukemia stem cells (LSCs), a chemoresistant subpopulation capable of initiating and re-establishing disease.2 Studies correlating LSC proportion within individual patients to relapse-free survival have established that higher proportions of LSCs at diagnosis are associated with inferior relapse-free survival.3 Thus, as LSCs resist standard therapy, devising new therapeutic strategies that ablate LSCs are likely to improve outcomes. We have shown previously that LSC survival is extensively dependent on constitutively active NF-κB.4 Indeed, preclinical agents such as parthenolide (PTL) that potently suppress NF-κB can eliminate LSCs in vitro while preserving normal hematopoietic stem cell function.5 Despite its in vitro efficacy, PTL exhibits poor solubility, high reactivity with serum and poor pharmacokinetics6 that make it insufficiently bioavailable, limiting its in vivo use. Furthermore, LSCs preferentially reside in the bone marrow (BM) niche, a microenvironment that simultaneously supports LSC survival and provides chemoprotection.7 To overcome this protective effect, in this study, we evaluated whether encapsulation of PTL into nanoparticles and using a BM-directed multistage vector (MSV) system (MSV-PTL) would deliver active PTL at sufficiently levels to ablate LSCs in vivo.

Primary AML cells were obtained with informed consent and Institutional Review Board approval from Weill Cornell Medical College-New York Presbyterian Hospital. Primary cryopreserved AML samples were thawed and prepared for xenotransplants as described previously.13 Nonobese diabetic/severe combined iImmunodeficiency mice were then injected via tail vein (5–10 animals per cohort). Treatment with MSV or MSV-PTL (one billion particles) was started 5 weeks after transplantation and mice were treated once every 2 weeks for 4 weeks. The presence of human cells was evaluated by flow cytometry. For the secondary transplants, equal numbers of human cells were injected (5 animals per cohort). The percentage of human AML cells was determined by staining the cells with antibodies for PE-Cy5 rat anti-mouse CD45 (eBiosciences, San Diego, CA, USA) and APC-H7 anti-human CD45 (BD Biosciences, San Jose, CA, USA). For viability, Annexin V-FITC (BD Biosciences) and 7-aminoactinomycin (Thermo Fisher Scientific, Waltham, MA, USA) were used. For intracellular assays, cells were fixed with 4% formaldehyde and permeabilized with methanol. Analyses and graphs were performed using GraphPad Software, Inc. (La Jolla, CA, USA) to evaluate the significance. The specific test utilized is indicated in the figure legends *P<0.05, **P<0.01. (Additional methods can be found in the Supplementary Information).

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Acknowledgements

We are supported by Leukemia and Lymphoma Society (MLG, GJR and HS), WCMC-TMHRI Pilot grant (MLG and HS), US National Institutes of Health (NIH) through the NIH Director's New Innovator Award Program, 1 DP2 OD007399-01 (MLG) and National Cancer Institute (R21 CA158728-01A1; MLG). MLG is a V Foundation Scholar. PAC is funded by NCI/NIH: R01 CA158275 and COBRE NIH/NIGMS: P20GM109005.

Author contributions

HZ and SS performed the experiments. GZ, CM, DGG and XL generated the nanoparticles. All authors participated in the design and analysis of various experiments. HZ, GJR, HS and MLG wrote the paper.

Author information

Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    H Zong, S Sen, G J Roboz & M L Guzman

  2. Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX, USA

    G Zhang, C Mu, X Liu, M Ferrari & H Shen

  3. University of Arkansas for Medical Sciences, College of Pharmacy, Little Rock, AR, USA

    Z F Albayati & P A Crooks

  4. Institute of Molecular Medicine, The University of Texas-Houston Medical School, Houston, TX, USA

    D G Gorenstein

  5. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    M Ferrari

  6. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA

    H Shen

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  1. H Zong
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Corresponding author

Correspondence to M L Guzman.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Zong, H., Sen, S., Zhang, G. et al. In vivo targeting of leukemia stem cells by directing parthenolide-loaded nanoparticles to the bone marrow niche. Leukemia 30, 1582–1586 (2016). https://doi.org/10.1038/leu.2015.343

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