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Targeted cancer cell delivery of arsenate as a reductively activated prodrug

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Abstract

Nanoformulations, prodrugs, and targeted therapies are among the most intensively investigated approaches to new cancer therapeutics. Human ferritin has been used extensively as a nanocarrier for the delivery of drugs and imaging agents to cancerous tumor cells both in vitro and in vivo. We report exploitation of the native properties of ferritin, which can be co-loaded with simple forms of iron (FeOOH) and arsenic (arsenate) in place of the native phosphate. The As(III) form arsenic trioxide has been successfully used to treat one blood cancer, but has so far proven too systemically toxic for use on solid tumors in the clinic. The As(V) form, arsenate, on the other hand, while much less systemically toxic upon bolus injection has also proven ineffective for cancer therapy. We extended the C-terminal ends of the human ferritin subunits with a tumor cell receptor targeting peptide and loaded this modified ferritin with ~ 800 arsenates and ~ 1100 irons. Our results demonstrate targeting and uptake of the iron, arsenate-loaded modified human ferritin by breast cancer cells. At the same arsenic levels, the cytotoxicity of the iron, arsenate-loaded human ferritin was equivalent to that of free arsenic trioxide and much greater than that of free arsenate. The iron-only loaded human ferritin was not cytotoxic at the highest achievable doses. The results are consistent with the receptor-targeted human ferritin delivering arsenate as a reductively activated ‘prodrug’. This targeted delivery could be readily adapted to treat other types of solid tumor cancers.

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Acknowledgements

This article is dedicated to the memory of Beth A. Goins. This research was supported by a Grant from the Cancer Prevention and Research Institute of Texas (RP110165). The Biophotonics Core facility and Flow Cytometry Core facility at the University of Texas at San Antonio (UTSA) are supported by a Grant from the National Institute on Minority Health and Health Disparities from the National Institutes of Health (G12MD007591). H. Shipley in the UTSA Department of Civil and Environmental Engineering, and K. Nash in the UTSA Department of Physics and Astronomy provided access to ICP-OES and DLS instrumentation, respectively.

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  1. Department of Chemistry, University of Texas at San Antonio, San Antonio, TX, USA

    Daniela Cioloboc & Donald M. Kurtz Jr.

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  1. Daniela Cioloboc
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  2. Donald M. Kurtz Jr.
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Correspondence to Donald M. Kurtz Jr..

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Cioloboc, D., Kurtz, D.M. Targeted cancer cell delivery of arsenate as a reductively activated prodrug. J Biol Inorg Chem 25, 441–449 (2020). https://doi.org/10.1007/s00775-020-01774-3

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  • DOI: https://doi.org/10.1007/s00775-020-01774-3

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