Cytotoxic sub-nanometer aqueous platinum clusters as potential antitumoral agents

[EN] Ligand-free sub-nanometer metal clusters (MCs) of Pt, Ir, Rh, Au and Cu, are prepared here in neat water and used as extremely active (nM) antitumoral agents for HeLa and A2870 cells. The preparation just consists of adding the biocompatible polymer ethylene-vinyl alcohol (EVOH) to an aqueous solution of the corresponding metal salt, to give liters of a MC solution after filtration of the polymer. Since the MC solution is composed of just neat metal atoms and water, the intrinsic antitumoral activity of the different sub-nanometer metal clusters can now fairly be evaluated. Pt clusters show an IC50 of 0.48 mu M for HeLa and A2870 cancer cells, 23 times higher than that of cisplatin and 1000 times higher than that of Pt NPs, and this extremely high cytotoxicity also occurs for cisplatin-resistant (A2870 cis) cells, with a resistance factor of 1.4 (IC50 = 0.68 mu M). Rh and Ir clusters showed an IC50 similar to 1 mu M. Combined experimental and computational studies support an enhanced internalization and cytotoxic activation. This work was supported by MINECO (Spain, Projects CTQ 2017-86735-P [AEI/FEDER, UE], PID2020-115010RB-I00, BEAGAL 18/00211, MAT2017-87579-R, IJC2018-036514-I and SEV-2016-0683). Financial support by the project PID2020-115100GB-I00 (funded by Spanish MCIINN, MCIN/AEI/10.13039/501100011033MICIIN) is acknowledged. STEM studies were performed at the DME-UCA node of the National Unique Infrastructure for Electron Microscopy of Materials, ELECMI. Theoretical calculations were conducted in the Poznan Supercomputing Center and in the Plataforma Andaluza de Bioinformatica located at the Universidad Malaga, Spain. The proteomic analysis was performed in the proteomics facility of the SCSIE University of Valencia. We gratefully acknowledge ALBA synchrotron for allocating beamtime and CL AE SS beamline staff for their technical support during our experiment. R. G. thanks ITQ for the concession of a contract. We also thank M. T. Minguez-Hernandez (SCSIE, UV) for the preparation of ultramicrotome samples. Greco, R.; García-Laínez, G.; Oliver-Meseguer, J.; Marini, C.; Domínguez, I.; Lopez-Haro, M.; Hernandez-Garrido, JC... (2022). Cytotoxic sub-nanometer aqueous platinum clusters as potential antitumoral agents. Nanoscale Advances. 4(24):5281-5289. https://doi.org/10.1039/d2na00550f