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1.
Inorg Chem ; 61(37): 14705-14717, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36047922

RESUMO

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 platinum-coated 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.


Assuntos
Antineoplásicos , Pró-Fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbono , Linhagem Celular Tumoral , Cisplatino/química , Humanos , Hipóxia , Ligantes , Metronidazol/farmacologia , Platina/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia
2.
J Med Chem ; 65(12): 8227-8244, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35675651

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides , Antineoplásicos , Compostos de Platina , Pró-Fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Desenho de Fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Compostos de Platina/farmacologia , Pró-Fármacos/farmacologia
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