The Pt(IV) prodrug of kiteplatin, cis-trans-cis-[PtCl2(RS-Ibuprofen-H)2(cis-1,4-DACH)], having in the axial positions two molecules of Ibuprofen, has been synthesised, characterized and tested in vitro. The aim was to potentiate the cytotoxic effect of kiteplatin with the anti-inflammatory activity of Ibuprofen. The reduction potential of the conjugate resulted comparable to those of other reported Pt(IV) carboxylate complexes, ensuring in vivo stability in blood during transport and intracellular reduction with release of the active species. The cytotoxic activity of the complex resulted remarkably potentiated reaching nanomolar activity. It is possible that the coordinated Ibuprofen molecules promote the transport and the accumulation of the complex in tumor cells by increasing its lipophilicity. In addition to the increased uptake, Ibuprofen could also exert an anti-inflammatory action mediated by inhibition of the COX enzymes which are overexpressed in tumors. The use of a conjugate with Pt-bound Ibuprofen can ensure similar cellular uptake and biodistribution for both the anti-inflammatory and the cytotoxic drugs in the exact ratio of 2:1.

Synthesis, characterization, and in vitro cytotoxicity of a Kiteplatin-Ibuprofen Pt(IV) prodrug

Denora, Nunzio;Iacobazzi, Rosa Maria;Ditaranto, Nicoletta;Margiotta, Nicola
;
2018-01-01

Abstract

The Pt(IV) prodrug of kiteplatin, cis-trans-cis-[PtCl2(RS-Ibuprofen-H)2(cis-1,4-DACH)], having in the axial positions two molecules of Ibuprofen, has been synthesised, characterized and tested in vitro. The aim was to potentiate the cytotoxic effect of kiteplatin with the anti-inflammatory activity of Ibuprofen. The reduction potential of the conjugate resulted comparable to those of other reported Pt(IV) carboxylate complexes, ensuring in vivo stability in blood during transport and intracellular reduction with release of the active species. The cytotoxic activity of the complex resulted remarkably potentiated reaching nanomolar activity. It is possible that the coordinated Ibuprofen molecules promote the transport and the accumulation of the complex in tumor cells by increasing its lipophilicity. In addition to the increased uptake, Ibuprofen could also exert an anti-inflammatory action mediated by inhibition of the COX enzymes which are overexpressed in tumors. The use of a conjugate with Pt-bound Ibuprofen can ensure similar cellular uptake and biodistribution for both the anti-inflammatory and the cytotoxic drugs in the exact ratio of 2:1.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/208882
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