Mitoxantrone-loaded superparamagnetic iron oxide nanoparticles as drug carriers for cancer therapy: Uptake and toxicity in primary human tubular epithelial cells

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) are in use for many clinical diagnostic and experimental therapeutic applications, for example, for targeted drug delivery. To analyze the cellular responses to mitoxantrone-carrying SPIONs (SPION-MTO), and to the drug released from SPIONs, we used an in vitro system that allows comparison of primary human cells with different endocytotic capacities, namely, epithelial cells from proximal and distal parts of the nephron. SPIONs were selectively and rapidly internalized by proximal tubular cells with high endocytotic potential, but not by distal tubular cells. Uptake did not affect cell viability or morphology. In both cell types, free MTO (10-100 nM) induced double-strand DNA breaks and senescence, cell hypertrophy and reduced cell proliferation. However, cadherin-mediated cell-cell adhesion, cytoskeletal structures or polarity of the cells were not affected. Interestingly, a comparable response was also observed upon treatment with SPION-MTO and was independent of uptake of the particles. The effect of SPION-MTO on cells which did not internalize particles was primarily related to the release of MTO from drug-coated particles upon incubation in serum-containing cell growth medium. In conclusion, we show that whereas the uptake of SPIONs does not affect cellular functions or viability, the toxicity of drug-loaded SPIONs depends essentially on the type of drug bound to nanoparticles. Due to the relatively low systemic toxicity of MTO, the effects of MTO-SPIONs on human tubular cells were moderate, but they may become clinically relevant when more nephrotoxic drugs are bound to SPIONs.

Inhibition of oxygen-sensing prolyl hydroxylases increases lipid accumulation in human primary tubular epithelial cells without inducing ER stress

“…These cells differ by their expression of cell-cell adhesion molecules: in human kidneys, proximal tubular cells express N-cadherin, whereas distal tubular cells express E-cadherin (Nouwen et al 1993). In isolated tubular epithelial cells, the differential expression of cadherins is maintained, as we have shown earlier (Cicha et al 2016;Keller et al 2012). Based on their differential adhesion to plastic dishes, subcultures of more adherent distal and less adherent proximal hPTEC were obtained (Grampp and Goppelt-Struebe 2018) and analyzed for the mRNA expression of 12 markers specific for proximal or distal tubular cells (Lake et al 2019;Lee et al 2015) (Electronic Supplementary Material,.…”

<p>Magnetic Field Promotes Migration of Schwann Cells with Chondroitinase ABC (ChABC)-Loaded Superparamagnetic Nanoparticles Across Astrocyte Boundary in vitro</p>

“…Currently, SPIONs can be artificially driven by an external MF; this approach has been used in drug release, cell separation, and magnetic resonance imaging. 41,42 However, studies showed that in the absence of an appropriate coating nanoparticles tend to form irreversible agglomerates. 43 Therefore, it is essential to modify SPIONs with polymers to increase their stability and manipulate their surface properties to improve cell and material interface.…”

Iron Oxide Nanoparticles for Biomedical Applications: A Perspective on Synthesis, Drugs, Antimicrobial Activity, and Toxicity

“…Current investigations have also synthesized IONPs employing different shells with anticancer agents conventionally administered, such as β-cyclodextrin [ 135 ], carmustine [ 136 ], cetuximab [ 137 , 138 , 139 ], cytarabine [ 140 ], daunomycin [ 141 ], docetaxel [ 142 , 143 ], epirubicin [ 144 ], 5-fluorouracil [ 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 ], gemcitabine [ 22 , 154 , 155 , 156 , 157 , 158 ], methotrexate [ 159 , 160 , 161 ], mitoxantrone [ 162 , 163 , 164 , 165 ] and paclitaxel [ 27 , 104 , 166 , 167 , 168 , 169 , 170 , 171 , 172 ]. It is noteworthy, however, that these nanosystems demonstrate magnetic properties only in the presence of external magnetic fields to prevent agglomerations of nanoparticles [ 111 ] and to allow a satisfactory performance in the target sites.…”

“…Positively charged IONPs were shown to be more toxic, since they undergo nonspecific interactions and adsorptive endocytosis with the negatively charged cell membrane, thus increasing their intracellular accumulation and affecting cell membrane integrity [ 218 ]. Other factors such as concentration, type of coating, form of administration, as well as the cell line may explain the different results for IONPs toxicity [ 21 , 22 , 23 , 25 , 26 , 66 , 71 , 72 , 96 , 97 , 98 , 163 , 214 , 215 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 ], as shown in Table 1 .…”