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Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration

Kiteplatin, [PtCl(2)(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve t...

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Autores principales: Barbanente, Alessandra, Gandin, Valentina, Ceresa, Cecilia, Marzano, Cristina, Ditaranto, Nicoletta, Hoeschele, James D., Natile, Giovanni, Arnesano, Fabio, Pacifico, Concetta, Intini, Francesco P., Margiotta, Nicola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266928/
https://www.ncbi.nlm.nih.gov/pubmed/35806087
http://dx.doi.org/10.3390/ijms23137081
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author Barbanente, Alessandra
Gandin, Valentina
Ceresa, Cecilia
Marzano, Cristina
Ditaranto, Nicoletta
Hoeschele, James D.
Natile, Giovanni
Arnesano, Fabio
Pacifico, Concetta
Intini, Francesco P.
Margiotta, Nicola
author_facet Barbanente, Alessandra
Gandin, Valentina
Ceresa, Cecilia
Marzano, Cristina
Ditaranto, Nicoletta
Hoeschele, James D.
Natile, Giovanni
Arnesano, Fabio
Pacifico, Concetta
Intini, Francesco P.
Margiotta, Nicola
author_sort Barbanente, Alessandra
collection PubMed
description Kiteplatin, [PtCl(2)(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis,trans,cis-[PtCl(2)(OBz)(2)(cis-1,4-DACH)] (1; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·10(6) LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay.
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spelling pubmed-92669282022-07-09 Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration Barbanente, Alessandra Gandin, Valentina Ceresa, Cecilia Marzano, Cristina Ditaranto, Nicoletta Hoeschele, James D. Natile, Giovanni Arnesano, Fabio Pacifico, Concetta Intini, Francesco P. Margiotta, Nicola Int J Mol Sci Article Kiteplatin, [PtCl(2)(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis,trans,cis-[PtCl(2)(OBz)(2)(cis-1,4-DACH)] (1; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·10(6) LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay. MDPI 2022-06-25 /pmc/articles/PMC9266928/ /pubmed/35806087 http://dx.doi.org/10.3390/ijms23137081 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barbanente, Alessandra
Gandin, Valentina
Ceresa, Cecilia
Marzano, Cristina
Ditaranto, Nicoletta
Hoeschele, James D.
Natile, Giovanni
Arnesano, Fabio
Pacifico, Concetta
Intini, Francesco P.
Margiotta, Nicola
Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration
title Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration
title_full Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration
title_fullStr Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration
title_full_unstemmed Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration
title_short Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration
title_sort improvement of kiteplatin efficacy by a benzoato pt(iv) prodrug suitable for oral administration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266928/
https://www.ncbi.nlm.nih.gov/pubmed/35806087
http://dx.doi.org/10.3390/ijms23137081
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