Evaluation of the biological profile of coordination complexes: an approach in 2D and 3D cell models

Abstract

In vitro cell cultures are fundamental techniques in developing new drug candidates. Traditional cell culture methods use a two-dimensional (2D) monolayer. Today, this method has become standard technology in the life sciences, making continuous improvements. However, due to the inherent flaws of traditional 2D culture, this methodology cannot correctly mimic the architecture and microenvironments of the human organism. This limitation makes 2D cultured cells different from cells that grow in vivo in terms of morphology, proliferation, cellular and matrix interactions, differentiation, among other aspects. As a result of these conditions, about 95% of new anticancer candidates fail clinical trials despite robust indications of activity in preclinical in vitro models. Thus, the continuous development of tumor cell culture techniques is vital. In this context, 3D cultures models (spheroids and organoids) bring a new perspective to understanding the in vitro biological profile. Both generate physiologically relevant results since these models can simulate the main features of an in vivo environment, including cell-cell and cell-extracellular matrix interactions. They possibly lead to better screening and success of promising candidates in vivo and clinical trials. The research group Coordinating Compounds in Medicinal Chemistry (CCQM) has been specializing in investigating the mechanism of action of biologically active complexes in the combat against cancer. However, our data are limited to information from monolayer assays. Therefore, this project proposes the synthesis and evaluation of the behavior of several coordination compounds, including metalloporphyrin compounds, Pd(II), Ru(II), Ir(III), Eu(III), and Tb(III) complexes. All the compounds will be tested against tumor and non-tumor cell lines. The most promising compounds will be analyzed in a more representative biological environment through 3D cell culture (spheroids and organoids). Additionally, such complexes will have their biological action profile evaluated through cell morphology, cytotoxicity/cytostatic, cell cycle influence, and cell death mechanism assays. In addition, interaction studies against biomolecules (DNA, DNA-topoisomerases, and HSA) will be carried out by different techniques. These studies will bring a new horizon in the design and understanding of the mode of action of coordination compounds with possible antitumor action. (AU)