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

Abstract

Kiteplatin, [PtCl2(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-[PtCl2(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 (2·106 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.

Flavin-Conjugated Pt(IV) Anticancer Agents

“…Inspiring examples were reported by Zhu et al, who brilliantly demonstrated that the anchoring of photoactive molecules such as porphyrins or coumarins to a Pt­(IV) center provided a handle to switch on and enhance the antiproliferative activity of such derivatives. Others reported Pt­(IV) complexes conjugated with bioactive ligands such as drugs, − vitamin analogues, enzyme inhibitors, − or imaging agents . Also in the case of these dual-action agents, the biological activity strongly depends on the redox chemistry of the Pt ion.…”

Stimuli-responsive platinum and ruthenium complexes for lung cancer therapy

“…Complex 46 was found significantly more effective than cisplatin against A549 cells in vitro with an IC 50 value of 0.05 μM ( Margiotta et al, 2016 ). In vivo anticancer activity of complex 46 after oral administration on LLC-bearing mouse model was comparable with intraperitoneal administration of cisplatin ( Barbanente et al, 2022 ). These results suggest that complex 46 have potential as oral anticancer agents.…”

Flavin-conjugated Pt(IV) anticancer agents

“…Inspiring examples were reported by Zhu who brilliantly demonstrated that anchoring of photoactive molecules such as porphyrins, 13 or coumarins 14 to a Pt(IV) center provided a handle to switch on and enhance the antiproliferative activity of such derivatives. Others reported Pt(IV) complexes conjugated with bioactive ligands such as drugs, [15][16][17][18][19][20] vitamin analogues, 21 enzyme inhibitors [22][23][24] or imaging agents. 25 Also in the case of these dual-action agents, the biological activity strongly depends on the redox chemistry of the Pt ion.…”