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Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells

Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroli...

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Autores principales: Khoury, Aleen, Sakoff, Jennette A., Gilbert, Jayne, Karan, Shawan, Gordon, Christopher P., Aldrich-Wright, Janice R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853328/
https://www.ncbi.nlm.nih.gov/pubmed/36559273
http://dx.doi.org/10.3390/pharmaceutics14122780
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author Khoury, Aleen
Sakoff, Jennette A.
Gilbert, Jayne
Karan, Shawan
Gordon, Christopher P.
Aldrich-Wright, Janice R.
author_facet Khoury, Aleen
Sakoff, Jennette A.
Gilbert, Jayne
Karan, Shawan
Gordon, Christopher P.
Aldrich-Wright, Janice R.
author_sort Khoury, Aleen
collection PubMed
description Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO(3))(2), (2) exhibiting the lowest GI(50) of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 2 being 1000-fold more active in the HT29 colon cancer cell line. Against the MCF-7 breast cancer cell line, in which high levels of biotin receptors are expressed, 2, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO(3))(2), (3), and [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO(3))(2), (4) exhibited enhanced activity compared to their platinum(II) cores, with 4 being 6-fold more active than its platinum(II) precursor. Furthermore, 3 exhibited 3-fold greater selectivity towards MCF-7 breast cancer cells compared to MCF10A breast healthy cells, and this was further confirmed by platinum uptake studies, which showed 3 to have almost 3-fold greater uptake in MCF-7 cells, compared to MCF10A cells. The results show that lipophilicity and selectivity both contributed to the cellular uptake of 1–4; however, this was not always translated to the observed cytotoxicity.
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spelling pubmed-98533282023-01-21 Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells Khoury, Aleen Sakoff, Jennette A. Gilbert, Jayne Karan, Shawan Gordon, Christopher P. Aldrich-Wright, Janice R. Pharmaceutics Article Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO(3))(2), (2) exhibiting the lowest GI(50) of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 2 being 1000-fold more active in the HT29 colon cancer cell line. Against the MCF-7 breast cancer cell line, in which high levels of biotin receptors are expressed, 2, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO(3))(2), (3), and [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO(3))(2), (4) exhibited enhanced activity compared to their platinum(II) cores, with 4 being 6-fold more active than its platinum(II) precursor. Furthermore, 3 exhibited 3-fold greater selectivity towards MCF-7 breast cancer cells compared to MCF10A breast healthy cells, and this was further confirmed by platinum uptake studies, which showed 3 to have almost 3-fold greater uptake in MCF-7 cells, compared to MCF10A cells. The results show that lipophilicity and selectivity both contributed to the cellular uptake of 1–4; however, this was not always translated to the observed cytotoxicity. MDPI 2022-12-12 /pmc/articles/PMC9853328/ /pubmed/36559273 http://dx.doi.org/10.3390/pharmaceutics14122780 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
Khoury, Aleen
Sakoff, Jennette A.
Gilbert, Jayne
Karan, Shawan
Gordon, Christopher P.
Aldrich-Wright, Janice R.
Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells
title Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells
title_full Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells
title_fullStr Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells
title_full_unstemmed Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells
title_short Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells
title_sort potent platinum(iv) prodrugs that incorporate a biotin moiety to selectively target cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853328/
https://www.ncbi.nlm.nih.gov/pubmed/36559273
http://dx.doi.org/10.3390/pharmaceutics14122780
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