Abstract
Tumor oxygenation is a critical issue for enhancing radiotherapy (RT) effectiveness. Alternating RT with hyperthermia improves tumor radiosensitivity by inducing a massive vasodilation of the neoangiogenic vasculature provided the whole tumor is properly heated. The aim of this work was to develop superparamagnetic oxygen-loaded nanobubbles (MOLNBs) as innovative theranostic hyperthermic agents to potentiate tumor oxygenation by direct intracellular oxygen administration. Magnetic oxygen-loaded nanobubbles were obtained by functionalizing dextran-shelled and perfluoropentane-cored nanobubbles with superparamagnetic iron oxide nanoparticles. Magnetic oxygen-loaded nanobubbles with sizes of about 380 nm were manufactured, and they were able to store oxygen and in vitro release it with prolonged kinetics. In vitro investigation showed that MOLNBs can increase tissue temperature when exposed to radiofrequency magnetic fields. Moreover, they are easily internalized by tumor cells, herein releasing oxygen with a sustained kinetics. In conclusion, MOLNBs can be considered a multimodal theranostic platform since, beyond their nature of contrast agent for magnetic resonance imaging due to magnetic characteristics, they showed echogenic properties and can be visualized using medical ultrasound.
Highlights
Oncological hyperthermia (HT) is a therapy consisting in increasing tumor temperature between 40°C and 45°C for about 1 hour in two to three weekly sessions often concomitantly with radiotherapy (RT) and sometimes radiochemotherapy (Falk and Issels, 2001; Hildebrandt et al, 2002; van der Zee, 2002; Wust et al, 2002).Effectiveness is critically related to the ability of heating the tumor almost uniformly and persistently during the HT session
The need for endogenous heat generation mechanisms led to the investigation of the so-called magnetic fluid hyperthermia (MFH), consisting in the in situ administration of a stable colloidal suspension of biocompatible superparamagnetic iron oxide nanoparticles (SPIONs), which can be activated by external magnetic fields (Hildebrandt et al, 2002)
Being tumor oxygenation one of the main targets of the hyperthermic treatment, here we investigated the use of oxygen nanocarriers “decorated” with SPIONs, hereinafter named magnetic oxygen-loaded nanobubbles (MOLNBs), which combined the magnetic-based increase in temperature with a direct oxygenation effect in the tumor volume
Summary
Oncological hyperthermia (HT) is a therapy consisting in increasing tumor temperature between 40°C and 45°C for about 1 hour in two to three weekly sessions often concomitantly with radiotherapy (RT) and sometimes radiochemotherapy (Falk and Issels, 2001; Hildebrandt et al, 2002; van der Zee, 2002; Wust et al, 2002).Effectiveness is critically related to the ability of heating the tumor almost uniformly and persistently during the HT session. Oncological hyperthermia (HT) is a therapy consisting in increasing tumor temperature between 40°C and 45°C for about 1 hour in two to three weekly sessions often concomitantly with radiotherapy (RT) and sometimes radiochemotherapy (Falk and Issels, 2001; Hildebrandt et al, 2002; van der Zee, 2002; Wust et al, 2002). External heating devices based on microwaves, radiofrequency (RF), ultrasound (US), or infrared are often inadequate for treating the whole tumor volume, especially deep-seated ones (Wust et al, 2002), and the physiological vasodilatory-based temperature control can be in MOLNBs Enhance Tumor Oxygenation principle counteracted, it would require multisite direct invasive temperature monitoring, which is uncomfortable, harmful, and possibly unethical. The physical bases and the possibility of tailoring treatments based on the fine tuning of a few parameters are well described in the literature (Spirou et al, 2018)
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