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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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/12/2780 |
| _version_ | 1797455705339330560 |
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| author | Aleen Khoury Jennette A. Sakoff Jayne Gilbert Shawan Karan Christopher P. Gordon Janice R. Aldrich-Wright |
| author_facet | Aleen Khoury Jennette A. Sakoff Jayne Gilbert Shawan Karan Christopher P. Gordon Janice R. Aldrich-Wright |
| author_sort | Aleen Khoury |
| collection | DOAJ |
| 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)(1<i>S</i>,2<i>S</i>-diaminocyclohexane)(biotin)(hydroxido)](NO<sub>3</sub>)<sub>2</sub>, (<b>2</b>) exhibiting the lowest GI<sub>50</sub> of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with <b>2</b> 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, <b>2</b>, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1<i>S</i>,2<i>S</i>-diaminocyclohexane)(biotin)(hydroxido)](NO<sub>3</sub>)<sub>2</sub>, (<b>3</b>), and [Pt(5-methyl-1,10-phenanthroline)(1<i>S</i>,2<i>S</i>-diaminocyclohexane)(biotin)(hydroxido)](NO<sub>3</sub>)<sub>2</sub>, (<b>4</b>) exhibited enhanced activity compared to their platinum(II) cores, with <b>4</b> being 6-fold more active than its platinum(II) precursor. Furthermore, <b>3</b> 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 <b>3</b> 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 <b>1</b>–<b>4</b>; however, this was not always translated to the observed cytotoxicity. |
| first_indexed | 2024-03-09T15:58:09Z |
| format | Article |
| id | doaj.art-2cc6b9c95c964c2893856eb9badd2173 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T15:58:09Z |
| publishDate | 2022-12-01 |
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| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-2cc6b9c95c964c2893856eb9badd21732023-11-24T17:21:53ZengMDPI AGPharmaceutics1999-49232022-12-011412278010.3390/pharmaceutics14122780Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer CellsAleen Khoury0Jennette A. Sakoff1Jayne Gilbert2Shawan Karan3Christopher P. Gordon4Janice R. Aldrich-Wright5School of Science, Western Sydney University, Locked Bag 1797, Penrith South DC, NSW 2751, AustraliaCalvary Mater Hospital, Waratah, NSW 2298, AustraliaCalvary Mater Hospital, Waratah, NSW 2298, AustraliaTeaching and Research Technical Services, Western Sydney University, Locked Bag 1797, Penrith South DC, NSW 2751, AustraliaSchool of Science, Western Sydney University, Locked Bag 1797, Penrith South DC, NSW 2751, AustraliaSchool of Science, Western Sydney University, Locked Bag 1797, Penrith South DC, NSW 2751, AustraliaFour 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)(1<i>S</i>,2<i>S</i>-diaminocyclohexane)(biotin)(hydroxido)](NO<sub>3</sub>)<sub>2</sub>, (<b>2</b>) exhibiting the lowest GI<sub>50</sub> of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with <b>2</b> 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, <b>2</b>, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1<i>S</i>,2<i>S</i>-diaminocyclohexane)(biotin)(hydroxido)](NO<sub>3</sub>)<sub>2</sub>, (<b>3</b>), and [Pt(5-methyl-1,10-phenanthroline)(1<i>S</i>,2<i>S</i>-diaminocyclohexane)(biotin)(hydroxido)](NO<sub>3</sub>)<sub>2</sub>, (<b>4</b>) exhibited enhanced activity compared to their platinum(II) cores, with <b>4</b> being 6-fold more active than its platinum(II) precursor. Furthermore, <b>3</b> 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 <b>3</b> 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 <b>1</b>–<b>4</b>; however, this was not always translated to the observed cytotoxicity.https://www.mdpi.com/1999-4923/14/12/278056MESSbiotincancercellular accumulationcytotoxicitylipophilicity |
| spellingShingle | Aleen Khoury Jennette A. Sakoff Jayne Gilbert Shawan Karan Christopher P. Gordon Janice R. Aldrich-Wright Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells Pharmaceutics 56MESS biotin cancer cellular accumulation cytotoxicity lipophilicity |
| 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 | 56MESS biotin cancer cellular accumulation cytotoxicity lipophilicity |
| url | https://www.mdpi.com/1999-4923/14/12/2780 |
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