Rhamnose‐coated superparamagnetic iron‐oxide nanoparticles: an evaluation of their in vitro cytotoxicity, genotoxicity and carcinogenicity

Abstract

Tumor recurrence after the incomplete removal of a tumor mass inside brain tissue is the main reason that scientists are working to identify new strategies in brain oncologic therapy. In particular, in the treatment of the most malignant astrocytic tumor glioblastoma, the use of magnetic nanoparticles seems to be one of the most promising keys in overcoming this problem, namely by means of magnetic fluid hyperthermia (MFH) treatment. However, the major unknown issue related to the use of nanoparticles is their toxicological behavior when they are in contact with biological tissues. In the present study, we investigated the interaction of glioblastoma and other tumor cell lines with superparamagnetic iron-oxide nanoparticles covalently coated with a rhamnose derivative, using proper cytotoxic assays. In the present study, we focused our attention on different strategies of toxicity evaluation comparing different cytotoxicological approaches in order to identify the biological damages induced by the nanoparticles. The data show an intensive internalization process of rhamnose-coated iron oxide nanoparticles by the cells, suggesting that rhamnose moiety is a promising biocompatible coating in favoring cells' uptake. With regards to cytotoxicity, a 35% cell death at a maximum concentration, mainly as a result of mitochondrial damages, was found. This cytotoxic behavior, along with the high uptake ability, could facilitate the use of these rhamnose-coated iron-oxide nanoparticles for future MFH therapeutic treatments.

Are iron oxide nanoparticles safe? Current knowledge and future perspectives

“…DNA damage was neither observed after treatment of L-929 fibroblasts with bare or TEOS-coated ION (magnetite) [36] or in lymphoblastoid TK6 cells and primary human leukocytes treated with uncoated nanomagnetite [58]. More recently, Couto et al [27] also demonstrated absence of ION effects on genetic material of human T-lymphocytes reporting no chromosome aberrations in cells treated with PAA-coated and non-coated nanomagnetite for 48 h. In agreement with these studies, Paolini et al [40] reported absence of genotoxic and carcinogenic effects of rhamnose-coated ION (magnetite) on mouse fibroblast Balb/c-3T3 cells. Furthermore, a number of studies evaluating the potential mutagenicity induced by different ION by means of Ames test, with or without metabolic activation, were also reported with negative results [34,94,95].…”

“…A number of in vitro studies have associated cytotoxicity induced by ION with oxidative stress and ROS production [62][63][64]. Thus, an increased generation of ROS by ION exposure was previously observed in Chinese hamster ovary (CHO-K1) cells [65], murine macrophage J774 cells [66], different vascular endothelial cells [67,68], Chinese hamster lung cells [69], human lung A549 cells [43,70], brain microglia cells [71], and glial T98G and U251MG and bladder ECV304 cells [40]. However, other studies reported negative results on ROS production after ION treatment [72,73].…”

“…Szalay et al [34] found that ION (magnetite) induced moderate time-and concentrationdependent decrease in viability of Vero cells after 24 h exposure, and low generation of cytotoxicity was observed in L-929 fibroblasts treated with ION modified with different functional groups [35][36][37]. Similarly, decreases in viability were found in human alveolar epithelial A549 cells treated with ION (Fe 2 O 3 ) [38], in cultured rat astrocytes exposed to aminosilane-or starch-coated ION (magnetite) at physiological temperatures (34-40 • C) [39], in human glioblastoma (T98G and U251MG) and urinary bladder carcinoma (ECV304) cell lines after treatment with rhamnose-coated ION (magnetite) [40] and in human neuronal (SHSY5Y) and glial (A172) cells exposed to oleic acid-coated or silica-coated magnetite nanoparticles [41].…”

“…Free iron released from ION metabolisation can be incorporated to the normal cellular iron pool from the endocytic compartment [22]. Thus, ION exposure in a variety of cells caused elevated intracellular iron concentrations, dependent on the dose [25,32,40,79]. Therefore, the normal body capacity to manage iron should be taken into account when considering administration of high or frequently repeated doses of ION [20].…”

Toxicological assessment of silica-coated iron oxide nanoparticles in human astrocytes

“…Hence, it is possible that the serum proteins favour the silica coating degradation, thus causing a higher iron release from the nanoparticle core. Nevertheless, different issues such as cell type, intracellular medium pH or composition, nanoparticle composition or physical-chemical characteristics such as size, coating or aggregation capacity have been previously suggested to be other main factors influencing the iron release from ION (Geppert et al, 2011(Geppert et al, , 2009Paolini et al, 2016;Rosenberg et al, 2012;Singh et al, 2012).…”