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

Abstract

We report herein a Pt(IV) prodrug with metronidazole in axial positions Pt-Mnz. The nitroaromatic axial ligand was conjugated with a cisplatin scaffold to irreversibly reduce under hypoxic conditions, thereby retaining the Pt(IV) prodrug in the area of hypoxia. X-ray near-edge adsorption spectroscopy (XANES) on dried drug-preincubated tumor cell samples revealed a gradual release of cisplatin from the Pt-Mnz prodrug instead of rapid intracellular degradation. The ability of the prodrug to penetrate into three-dimensional (3D) spheroid cellular cultures was evaluated by a novel electrochemical assay via a platinumcoated carbon nanoelectrode, capable of single-cell measurements. Using a unique technique of electrochemical measurements in single tumor spheroids, we were able to both detect the real-time response of the axial ligand to hypoxia and establish the depth of penetration of the drug into the tumor model.

Photoinduced Reduction of Novel Dual-Action Riboplatin Pt(IV) Prodrug

“…To investigate the in-cell Pt 2+ species level, electrochemical detection could also be proposed. Recently, we reported a Pt 2+ species level quantification via PtNE in single cells, spheroids, and in mice xenografts. − Herein, we used PtNE to detect light-induced cisplatin release from a prodrug in real time.…”

“…51 This technique has proven to be effective in investigating the ability of various Pt(IV) prodrugs to accumulate cis-platin in cells and spheroids in vitro and in solid tumors in vivo. 52,53 In the current research, we applied the PtNE technique for the real-time monitoring of photoinduced drug metabolism in the tumor model. A novel PDT/PACT agent, Riboplatin, was designed, and its intracellular response to blue-light irradiation was estimated using nanoscale electrochemical measurements in spheroids.…”

“…Recently, we have developed a PtNE-based technique which is able to quantify Pt­(II) species in single cells, 3D tumor spheroids, and tumors in vivo . This technique has proven to be effective in investigating the ability of various Pt­(IV) prodrugs to accumulate cis -platin in cells and spheroids in vitro and in solid tumors in vivo. , …”

Biotinylated Pt(iv) prodrugs with elevated lipophilicity and cytotoxicity

“…36 We have previously determined extracellular reduction rate of several Pt(IV) prodrugs. 26,37 Thus, Pt(IV) prodrugs NP with one naproxen moiety in axial position demonstrated fast intracellular decay, while the introduction of biotin into the axial position of the Pt(IV) prodrug slows down intracellular reduction rate.…”

Nano- and Microsensors for In Vivo Real-Time Electrochemical Analysis: Present and Future Perspectives

“…The prodrug was found to penetrate more deeply than cisplatin. This research demonstrates a minimally invasive, real-time electrochemical technique for the study of platinum-based drugs that enables the possibility of determining the prospects of platinum-containing drugs by assessing their penetration using in vitro and in vivo models [ 126 , 127 ].…”