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Towards improved boron neutron capture therapy agents: evaluation of in vitro cellular uptake of a glutamine-functionalized carborane

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Abstract

Sodium borocaptate (BSH) is widely used for boron neutron capture therapy (BNCT) of brain tumors. One drawback is the large uptake by the liver causing a decrease of its availability at the tumor region as well as bringing about toxicity problems. A novel carborane-based compound containing a boron payload very similar to that of BSH has been synthesized and tested on rat glioma (C6) cells, hepatoma tissue culture (HTC) cells, and hepatocytes. The newly synthesized system consists of an o-carborane unit (C2B10H11, o-CB) conjugated to a glutamine residue through a proper spacer, namely, o-CB-Gln. As compared with BSH, it showed the same uptake by C6 cells, but a 50% decrease in uptake by HTC cells and an 80% decrease in uptake by healthy hepatocytes. On this basis o-CB-Gln appears an interesting candidate for BNCT of brain tumors as it is expected to have a therapeutic index analogous to that of BSH accompanied by a much lower liver toxicity.

Graphical Abstract

A novel carborane based compound, consisting in an o-carborane unit (C2B10H11, o-CB) conjugated to a glutamine residue through a proper spacer (namely o-CB-Gln) has been synthesized, characterized and tested on rat glioma (C6), hepatoma (HTC) and hepatocytes. As compared to sodium borocaptate (BSH), widely used for boron neutron capture therapy (BNCT) of brain tumors, the newly synthesized system showed the same uptake by C6 cells, but a 50% decrease by HTC and 80% decrease by healthy hepatocytes. On this basis o-CB-Gln appears an interesting candidate for BNCT of brain tumors as it is expected to have a therapeutic index analogous to BSH accompanied by a much lower liver toxicity.

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Acknowledgments

The authors gratefully acknowledge Regione Piemonte (project no. A97/2004) and Compagnia San Paolo for financial support. This work was supported by MIUR (PRIN and FIRB projects), Meditrans IP, EMIL, and DiMI EU NoEs.

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Authors and Affiliations

  1. Department of Chemistry IFM, University of Turin, Via Pietro Giuria 7, 10125, Turin, Italy

    Antonella Crivello, Carlo Nervi, Roberto Gobetto, Antonio Toppino & Silvio Aime

  2. Center for Molecular Imaging, University of Turin, via Nizza 52, 10126, Turin, Italy

    Simonetta Geninatti Crich, Iboya Szabo & Silvio Aime

  3. Department of General and Organic Chemistry, University of Turin, Via Pietro Giuria 7, 10125, Turin, Italy

    Antonio Toppino, Annamaria Deagostino & Paolo Venturello

  4. Department of Science and Drug Technology, University of Turin, Via Pietro Giuria 9, 10125, Turin, Italy

    Alessandro Barge

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  1. Antonella Crivello
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  2. Carlo Nervi
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  3. Roberto Gobetto
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Correspondence to Silvio Aime.

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Crivello, A., Nervi, C., Gobetto, R. et al. Towards improved boron neutron capture therapy agents: evaluation of in vitro cellular uptake of a glutamine-functionalized carborane. J Biol Inorg Chem 14, 883–890 (2009). https://doi.org/10.1007/s00775-009-0500-1

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  • DOI: https://doi.org/10.1007/s00775-009-0500-1

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