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

被引:9
作者
Barbanente, Alessandra [1 ]
Gandin, Valentina [2 ]
Ceresa, Cecilia [3 ]
Marzano, Cristina [2 ]
Ditaranto, Nicoletta [1 ]
Hoeschele, James D. [4 ]
Natile, Giovanni [1 ]
Arnesano, Fabio [1 ]
Pacifico, Concetta [1 ]
Intini, Francesco P. [1 ]
Margiotta, Nicola [1 ]
机构
[1] Univ Bari Aldo Moro, Dipartimento Chim, Via E Orabona 4, I-70125 Bari, Italy
[2] Univ Padua, Dipartimento Sci Farmaco, Via Marzolo 5, I-35131 Padua, Italy
[3] Univ Milano Bicocca, Scuola Med & Chirurg, Via Cadore 48, I-20900 Monza, Italy
[4] Eastern Michigan Univ, Dept Chem, Ypsilanti, MI 48197 USA
关键词
cisplatin; oxaliplatin; kiteplatin; antitumor drugs; oral administration; colorectal cancer; neurotoxicity; PLATINUM(IV) COMPOUNDS; DRUG; COMPLEXES; OXALIPLATIN; GLUTATHIONE; REDUCTION; DESIGN; DNA; NEUROTOXICITY; CYTOTOXICITY;
D O I
10.3390/ijms23137081
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 similar to 60% of the initial one only after 72 h incubation at 37 degrees 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 (similar to 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 degrees C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay.
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页数:15
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