Pt(IV) Prodrugs with Non-Steroidal Anti-inflammatory Drugs in the Axial Position

Abstract

We report herein the design, synthesis, and biological investigation of a series of novel Pt­(IV) prodrugs with non-steroidal anti-inflammatory drugs naproxen, diclofenac, and flurbiprofen, as well as these with stearic acid in the axial position. Six Pt­(IV) prodrugs 5–10 were designed, which showed superior antiproliferative activity compared to cisplatin as well as an ability to overcome tumor cell line resistance to cisplatin. By tuning the drug lipophilicity via variation of the axial ligands, the most potent Pt­(IV) prodrug 7 was obtained, with an enhanced cellular accumulation of up to 153-fold that of cisplatin and nanomolar cytotoxicity both in 2D and 3D cell cultures. Pt2+ species were detected at different depths of MCF-7 spheroids after incubation with Pt­(IV) prodrugs using a Pt-coated carbon nanoelectrode. Cisplatin accumulation in vivo in the murine mammary EMT6 tumor tissue of BALB/c mice after Pt­(IV) prodrug injection was proved electrochemically as well. The drug tolerance study on BALB/c mice showed good tolerance of 7 in doses up to 8 mg/kg.

Electrochemical Detection of a Novel Pt(IV) Prodrug with the Metronidazole Axial Ligand in the Hypoxic Area

“…Compared to the peak of cisplatin oxidation obtained in the cisplatin solutions (∼700 mV, Figure S42), a slight shift to the right is observed. This effect might be due to the intracellular metabolism of the drug, which was discussed previously. , …”

“…At different depths of the cellular spheroid, we recorded cyclic voltammograms from 400 to 1200 mV. The desired peak of Pt­(II)/Pt­(IV) oxidation is at 0.6–0.7 V vs Ag/AgCl, according to previously reported data , and preliminary experiments in cisplatin solutions. The calibration curve obtained from cyclic voltammetry (CV) in various cisplatin solutions allows us to quantify the Pt 2+ level inside the spheroid and thus compare the Pt 2+ accumulation level in spheroids, incubated with different Pt­(IV) prodrugs or cisplatin.…”

“…Electrochemical detection of Pt 2+ species in biological objects based on a platinized nanoelectrode allows one to quantify the amount of platinum-based drugs directly inside a therapeutic target and thus evaluate the drug efficacy. Having previously succeeded in the electrochemical detection of cisplatin in cells, spheroids, and in vivo, , in this work, we evaluate a hypoxia-induced metabolism of the Pt-Mnz prodrug using the same approach. The three-dimensional (3D) spheroid proved to be a useful tool for studying hypoxia and hypoxia-activated agents given those cellular cultures are relatively close models of real tumors. − …”

“…Then, the spheroids were treated with Pt-Mnz or cisplatin at 100 μM for 6 h at 37 °C in a 5% CO 2 incubator. After the incubation, spheroids were washed with PBS, followed by staining with FDCPt1 , diluted in PBS (100 μM) for 30 min at 37 °C and 5% CO 2 , according to the protocol of Shen et al (68). Then, the spheroids were washed again with PBS and fixed with 4% formaldehyde solution in PBS for 15 min at r.t. Spheroids were imaged on a Leica TCS SPE confocal microscopy system using a 488 nm excitation laser and a 10× objective.…”

“…Recently, we had developed a PtNE-based technique able to quantify Pt­(II) species in individual cells, cellular spheroids, tumors, and tissues in vivo . More recently, we used the PtNE-based technique to evaluate the efficacy of various Pt­(IV) prodrugs in a spheroid tumor model and in vivo …”