Synthetic beidellite clay as nanocarrier for delivery of antitumor oxindolimine-metal complexes.

Studies on the immobilization of oxindolimine‑copper(II) or zinc(II) complexes [ML] in synthetic beidellite (BDL) clay were developed to obtain a suitable inorganic carrier capable of promoting the modified-release of metallopharmaceuticals. Previous investigations have shown that the studied metal complexes are promising antitumor agents, targeting DNA, mitochondria, and some proteins. They can bind to DNA, causing oxidative damage via formation of reactive oxygen species (ROS). In mitochondria they lead to a decrease in membrane potential, acting as decoupling agents, and therefore efficiently inducing apoptosis. Additionally, they inhibit human topoisomerase IB and cyclin dependent kinases, proteins involved in the cell cycle. BDL clays in the sodium form were synthesized under hydrothermal conditions and characterized by a set of physicochemical techniques while the BDL-[ML] hybrid materials were prepared by ion exchange method. The characterization of pristine clay and the obtained hybrids were performed by Infrared, Raman, electron paramagnetic resonance and energy dispersive X-ray spectroscopies, thermogravimetric analysis, scanning electron microscopy, X-ray powder diffraction, specific surface area, zeta potential and surface ionic charge measurements. The [ML] release assays under the same cell incubation conditions were performed monitoring metals by X-ray fluorescence. The BDL-[CuL] hybrid materials were stable and able to derail tumor HeLa cells, with corresponding IC 50 values in the 0.11-0.41 mg mL -1 range. By contrast, the analogous hybrid samples of zinc(II) and the pristine BDL proved to be non-toxic facing the same cells. These results indicate a promising possibility of using synthetic beidellite as a carrier of such antitumor metal complexes.

Competing Interests: Declaration of Competing Interest The University of São Paulo (USP) has a Brazilian patent (BR PI 0600985–9 conceded on March 24th, 2020 – INPI Brazil) based on the oxindolimine-metal complexes with antitumor activity, prepared and investigated at Da Costa Ferreira's lab, at Institute of Chemistry - USP. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ana Maria da Costa Ferreira reports administrative support was provided by AUSPIN - Agencia USP de Inovação (University of São Paulo Innovation Agency). Ana Maria da Costa Ferreira reports a relationship with AUSPIN - Agencia USP de Inovação (University of São Paulo Innovation Agency) that includes: non-financial support. Ana Maria da Costa Ferreira has patent #Brazilian patent (BR PI 0600985-9 conceded on March 24th, 2020 – INPI Brazil) issued to non licensee or assignee.

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