Rational Design of Copper(II)-Uracil Nanoprocessed Coordination Polymers to Improve Their Cytotoxic Activity in Biological Media.

Carlos J. Gómez-García,Félix Zamora,María Luisa Marcos,Álvaro Somoza,José Martínez-Costas,Óscar Castillo,Miguel Vázquez López,Verónica G. Vegas,Ana Latorre,Jacobo Gómez,Pilar Amo-Ochoa

doi:10.1021/acsami.1c11612

Abstract

This work is focused on the rational structural design of two isostructural Cu(II) nano-coordination polymers (NCPs) with uracil-1-acetic acid (UAcOH) (CP1n) and 5-fluorouracil-1-acetic acid (CP2n). Suitable single crystals for X-ray diffraction studies of CP1 and CP2 were prepared under hydrothermal conditions, enabling their structural determination as 1D-CP ladder-like polymeric structures. The control of the synthetic parameters allows their processability into water colloids based on nanoplates (CP1n and CP2n). These NCPs are stable in water at physiological pHs for long periods. However, interestingly, CP1n is chemically altered in culture media. These transformations provoke the partial release of its building blocks and the formation of new species, such as [Cu(UAcO)2(H2O)4]·2H2O (Cu(II)-complex), and species corresponding to the partial reduction of the Cu(II) centers. The cytotoxic studies of CP1n versus human pancreatic adenocarcinoma and human uveal melanoma cells show that CP1n produces a decrease in the cell viability, while their UAcOH and Cu(II)-complex are not cytotoxic under similar conditions. The copper reduction species detected in the hydrolysis of CP1n are closely related to the formation of the reactive oxygen species (ROS) detected in the cytotoxic studies. These results prompted us to prepare CP2n that was designed to improve the cytotoxicity by the substitution of UAcO by 5-FUAcO, taking into account the anticancer activity of the 5-fluorouracil moiety. The new CP2n has a similar behavior to CP1n both in water and in biological media. However, its subtle structural differences are vital in improving its cytotoxic activity. Indeed, the release during the hydrolysis of species containing the 5-fluorouracil moiety provokes a remarkable increase in cellular toxicity and a significant increase in ROS species formation.

Highlights

The structural tunability of those nanostructures would enable the synthesis of nano-coordination polymers (NCPs) with different chemical and physical properties.[13,14]
Good-quality single crystals of CP1 and CP2 were prepared under hydrothermal conditions (120 °C for 3 and 2 days of reaction time, respectively), enabling their structural determination
Recent research has described that the cytotoxic effect of 5-FUAcOH was enhanced after being conjugated to biocompatible nanoparticles.[38]. As both Coordination polymers (CPs) present similar behaviors in the media, the objective is to verify if the transformation of the new CP2n in biological media produces an increase in cytotoxicity and reactive oxygen species (ROS) due to the presence of the new building block

Summary

■ INTRODUCTION

Coordination polymers (CPs) are based on the organized assembly of metal entities with organic and inorganic ligands giving rise to one-, two-, or three-dimensional architectures.[1−3] The large variety of the constituents allows the production of a huge structural variety, with almost a la carte physico-chemical properties,[4,5] thanks to the combination of metal centers and ligands.[6−9] A relatively common feature of most of the CPs is that they are quite insoluble in the reaction media, offering the possibility to form nanostructures in a one-pot bottom-up process[8,10,11] upon adjustment of the experimental conditions (i.e., temperature, concentration, and/or solvents).[12]. As both CPs present similar behaviors in the media, the objective is to verify if the transformation of the new CP2n in biological media produces an increase in cytotoxicity and ROS due to the presence of the new building block In this sense, Mel[202] and Panc-1 cells were treated with CP2n at distinct concentrations. This remarkable increase in ROS production could be the main cause of the increased toxicity in both cell lines (Figure 5c,d) These better results show the ability of CP2n to distribute 5-FUAcOH to the cancer cells as a consequence of the synergy produced by the transformations observed in biological media for the CPs, such as the reduction of Cu(II) observed in the cyclic voltammetry and the introduction of 5FuAcOH as a ligand. P values

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES