Analysis of the capability of doxorubicin delivered from magnetic nanocarriers to induce changes in cell death of colorectal cancer cells: a potential oncological therapy

Abstract

Colorectal cancer (CRC) is a disease with a great probability of treatment failure, leading to a high mortality rate. For this reason, science focuses on the development of new therapeutic strategies, including the use of magnetic nanoparticles (MNP), which are being studied for biomedical applications related to CRC. In previous studies, we observed that MNP functionalized with folic acid loaded with Doxorubicin (DOX), named DOX-MAG, internalized into cells derived from human CRC, leading to a decrease of live cell number compared to free DOX treatment even at lower concentrations. This work aims to deepen studies regarding the cell death triggered by DOX-MAG, elucidating the associated molecular mechanisms. By light and fluorescent microscopy, we observed that DOX-MAG induced an increase in the size of the nuclei at 8 hours of exposure, suggesting intensive polyploidization with a dose of 1 µM, being this response absent in free drug conditions at the same dose. In addition, after 24 hours, MNP stimulated the emergence of elongated protrusions, being the drug found in the cytosol and the nucleus, while the free drug is completely located in the nucleus. By western blot analysis, we observed an increment of cleaved PARP protein and the downregulation of the cell cycle inhibitor p21 after DOX-MAG uptake by the cells respect to free DOX conditions. These findings support the idea of faster cell death, with the apparition of apoptotic morphological features compared to free drug treatment. Summarizing, these results suggest that DOX-MAG markedly increased the effect of doxorubicin on human CRC models probably due to a different mode of action which may involve a dissimilar type of cell death. In this context, this contribution expands the knowledge of the behavior of nanocarriers in contact with in vitro models and proposes the DOX-MAG as potential theranostic agents for the improvement of cancer treatment.