A cancer specific oxaliplatin-releasing Pt(iv)-prodrug

Abstract

We prepared a Pt(iv)-prodrug, which under cancer specific conditions (elevated concentration of reactive oxygen species, ROS) releases a DNA-binding drug oxaliplatin as well as ROS-amplifying drugs p-quinone methide and N-alkylferrocenium. Due to the concerted action of these components, an excellent anticancer effect was achieved: IC50 = 0.4 ± 0.1 μM for human ovarian carcinoma A2780 cells. Importantly, the prodrug was found to be 45-fold less toxic to normal cells (HDFa).

Cytotoxicity and ROS production of novel Pt(IV) oxaliplatin derivatives with indole propionic acid

“…However, different selectivities and pharmacokinetics of the individual drugs can pose significant challenges in the application of combination therapy regimens. Oxidation of Pt(II) to Pt(IV) allows the covalent attachment of a second biologically active entity to the axial positions of the cisplatin-, carboplatin-or oxaliplatin-scaffold [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In addition to the simultaneous delivery of the Pt drug and the co-administered drug, Pt(IV) complexes have the advantages of a higher stability, lower toxicity, reduced side effects and potential for oral administration [3,4].…”

Current Approaches for Combination Therapy of Cancer: The Role of Immunogenic Cell Death

“…Oxaliplatin, as a chemotherapeutic agent that developed in the 1990s, possessing so highly sophisticated molecular mechanisms that they could induce cytotoxic effects against cancer cells, generates DNA adducts and activates the pro-apoptotic transcription factor [232,233]. It was indicated that oxaliplatin but not cisplatin mediates its antitumor effects through an immunogenic mode of tumor cell death in colorectal cancer [234].…”

Prodrug strategies for targeted therapy triggered by reactive oxygen species

“…Aminoferrocene arylboronic esters were coupled to PtIJIV) complexes that upon activation released cisplatin or oxaliplatin, prodrugs 18 and 19, respectively (Table 2). 50,51 After H 2 O 2activation, the resulting aminoferrocenes can donate two electrons to the acceptor PtIJIV) complex, liberating the PtIJII) drugs together with two aminoferrocenium complexes. The prodrugs act synergistically: 1) QMs scavenge the antioxidant system of cells, 2) aminoferrocenes generate ions able to catalyze the generation of ROS, and 3) the locally released PtIJII) complexes exert their cytotoxic activity selectively in targeted cancer cells.…”