Effectiveness and Safety of a Nontargeted Boost for a CXCR4-Targeted Magnetic Hyperthermia Treatment of Cancer Cells

Abstract

We investigate the effectiveness and safety of a novel magnetic hyperthermia (MHT) protocol, whereby a pretreatment with nontargeted magnetic nanoparticles (MNPs) is used to boost the subsequent iron loading of cancer cells by the targeted immuno-modified MNPs. As a model example, LN229 cancer cells express specific cell-surface receptors (CXCR4) at levels sufficient for diagnostic identification but insufficient for achieving 100% effective monotherapeutic MHT based on CXCR4-targeted MNPs. The nontargeted boost of the iron content overcomes this limitation of the targeted loading and is positively correlated with the maximum temperature reached during MHT treatment of LN229 cells. The effectiveness of the dual-population MHT strategy is validated by achieving a 100% lethal outcome for LN229 cancer cells 72 h after the treatment, while its safety is confirmed by the minimal cytotoxicity observed in control experiments with normal HK-2 cells or with an isotype-control targeting antibody. Systematic in vitro measurements thus demonstrate that the magnetic loading by targeted MNPs can be significantly increased by the nontargeted boost, even to double the iron concentration, while improving the effectiveness and maintaining the safety of MHT. This validation of the dual-population MHT strategy opens a novel materials-based pathway, unassisted by highly and nonselectively cytotoxic chemotherapeutic agents, to overcome the limited effectiveness of MHT for treating cancer cells that express only moderate levels of cell-surface receptors.

Magnetic Hyperthermia for Cancer Treatment: Main Parameters Affecting the Outcome of In Vitro and In Vivo Studies

“…There are indications of the existence of distinct thermal susceptibility between normal and cancer cells [ 20 , 21 ]. However, this is only true for a certain range of temperatures and it does not exclude the occurrence of side effects mediated by nanomaterials (NMs).…”

“…Fibroblasts, either from mouse origin [ 22 , 23 , 24 , 25 ] or from human [ 26 , 27 , 28 ] origin, are commonly used for this end. For targeted MHT studies, it may be more useful to use a cell line with a lower or even negative expression of the selected target, as this allows to simultaneously prove the selectivity of the treatment [ 21 , 25 ]. This type of study is particularly relevant when the selected target is also widely expressed in normal cells.…”

“…Improvements to targeted MHT efficiency can be achieved by combining it with other therapies [ 26 , 57 , 58 , 59 , 60 ]. The authors preferred to explore MHT in a mono-therapeutic context while combining targeted with non-targeted MNPs for increased efficiency [ 21 , 61 ]. By adjusting the amount of non-targeted nanoparticles as a magnetic boost for the targeted nanoparticles, it is possible to push up the temperature to the level necessary to induce consistent cancer cell death rates.…”

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons

“…When BT‐474 cells are treated with magnetic nanoparticles and mitomycin‐C in the presence or absence of hyperthermia, it is reported that hyperthermia intensifies inhibitory effects of nanoparticles and mitomycin‐C on the expression levels of MDR‐associated proteins . Inactivation of drug detoxification mechanisms, increase in the drug uptake, induction of apoptosis, enhancement of drug cytotoxicity, and reduction in cell membrane localization of MDR proteins are other effects mediated by hyperthermia, which circumvent MDR in various cancers …”

“…83 Inactivation of drug detoxification mechanisms, increase in the drug uptake, induction of apoptosis, enhancement of drug cytotoxicity, and reduction in cell membrane localization of MDR proteins are other effects mediated by hyperthermia, which circumvent MDR in various cancers. 84 The application of ultrasound therapy to enhance therapeutic efficacy against cancer cells has been the subject of various clinical investigations. This strategy has been applied as a hyperthermia-induction agent for direct treatment of tumors or as adjuvant therapy to increase the therapeutic efficacy when combined with chemotherapeutics.…”