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Pretargeting of necrotic tumors with biotinylated hypericin using 123I-labeled avidin: evaluation of a two-step strategy

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Summary

As an alternative to directly targeting of necrotic tissue using hypericin, we synthesized a conjugate of hypericin to biotin for use in a pretargeting approach. With this conjugate, we explored the possibility of a two-step pretargeting strategy using 123I-labeled avidin as effector molecule directed against necrotic RIF-1 tumors. Hypericin was conjugated to biotin-ethylenediamine in a straightforward coupling method using n-hydroxysuccinimide and dicyclohexylcarbodiimide. The necrosis avidity of the conjugate was first confirmed in necrotic liver tissue by means of fluorescence microscopy. Using autoradiography imaging and whole body-biodistribution, the accumulation of 123I-avidin in necrotic tumor tissue was evaluated 24 h after administration and 48 h after pretargeting with hypericin-biotin. Analysis of autoradiography images show a higher accumulation of 123I-avidin in pretargeted compared to nontargeted tissue. However, absolute accumulation of 123I-avidin in necrotic tumors was low as shown by biodistribution experiments. Direct injection of hypericin-biotin or biotin-fluorescein did not substantially improve 123I-avidin accumulation after pretargeting, pointing towards a poor penetration of avidin in necrotic tissue. Our results show the feasibility of a pretargeting technique using a small molecule as targeting agent. However, for a more efficient accumulation of the effector molecule in necrotic tissue, other pretargeting strategies need to be investigated.

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Acknowledgements

This research was funded by a PhD grant from the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen).

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Authors and Affiliations

  1. Laboratorium voor Farmaceutische Biologie, Faculteit Farmaceutische Wetenschappen, KU Leuven, Herestraat 49-bus 824, B-3000, Leuven, Belgium

    Thierry Marysael & Peter de Witte

  2. Laboratorium voor Radiofarmacie, Faculteit Farmaceutische Wetenschappen, K.U.Leuven, Leuven, Belgium

    Matthias Bauwens & Guy Bormans

  3. Departement Radiology, Faculteit Geneeskunde, K.U.Leuven, Leuven, Belgium

    Yicheng Ni

  4. Laboratorium voor Medicinale Chemie, K.U.Leuven, Leuven, Belgium

    Jef Rozenski

Authors
  1. Thierry Marysael
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  2. Matthias Bauwens
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  3. Yicheng Ni
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  4. Guy Bormans
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  5. Jef Rozenski
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  6. Peter de Witte
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Correspondence to Peter de Witte.

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Marysael, T., Bauwens, M., Ni, Y. et al. Pretargeting of necrotic tumors with biotinylated hypericin using 123I-labeled avidin: evaluation of a two-step strategy. Invest New Drugs 30, 2132–2140 (2012). https://doi.org/10.1007/s10637-011-9778-2

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  • DOI: https://doi.org/10.1007/s10637-011-9778-2

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