The letters N denote the nucleus, whereas the letters E indicate the endosomes. toxicity for the large MNPs, up to a concentration of 0.2 mg/mL. Cellular uptake experiments revealed that both MNPs penetrated the cells through endocytosis, in a time dependent manner and escaped the endosomes with a faster kinetics for large MNPs. Biodegradation of large MNPs inside cells involved an all-or-nothing mechanism. (MH) [5], relies Lesinurad sodium on the heat released by the MNPs exposed to an externally applied alternating magnetic field (AMF) which is used to increase the temperature of the cancer cells, up to a level at which apoptosis can be initiated. However, as Gilchrist et al. [4] initially pointed out in their seminal work, the efficient use of magnetic hyperthermia in clinical cancer treatment clearly demands MNPs with highly improved properties: (i) they should be able to deliver sufficient heat to completely destroy the tumor at the lowest particles dose and at safety levels of AMF; (ii) they must be biocompatible to easily circulate through the blood stream and (iii) they should be able to specifically target the cancer cells and to reliably provide a controlled intratumoral heat exposure [6,7]. The heating capabilities of MNPs under external AC magnetic field are quantified by the specific absorption rate (SAR) parameter (some authors use the term specific loss power (SLP) to describe the same physical reality), which provides a measure of the rate at which energy is absorbed per unit mass of the magnetic nanoparticles [8]. SAR values depend on MNPs structure, size, size distribution, shape and composition but also on the frequency (f) and the amplitude of the external AC magnetic field (H) applied Lesinurad sodium [9]. For clinical applications, it is largely accepted that the product between the frequency (f) and the magnetic field amplitude (H), tolerable for patients, should be smaller Smad1 than 5 109 Am?1s?1 [10], owing to the fact that Lesinurad sodium both, high frequency and high amplitude AMFs produce eddy currents in conducting media. Among all types of magnetic nanoparticles (MNPs) developed so far, Fe3O4 superparamagnetic iron oxide nanoparticles (SPION) are the only type of MNPs approved for clinical use by the US Food and Drug Administration [11]. They have already been tested in vivo for clinical MH therapy [12] due to their excellent biocompatibility and stability. This form of therapy was clinically approved in Europe for treatments of glioblastoma in 2011 and a clinical trial was also performed on prostate cancer [12]. However, it has been shown that the SAR values of spherical SPIONs with different diameters are relatively low (a few hundred W/g), and their heating power drastically decreases when the MNPs are localized into cells or tissues [13]. Consequently, in order to facilitate the complete elimination of the tumor, the magnetic hyperthermia has been used in conjunction with classical therapies (chemo and/or radio therapies), but in this case aggressive sides effects, have been observed. These limitations Lesinurad sodium can be overcome by using higher SPION doses in conjunction with higher AC magnetic fields amplitude and higher frequencies, but in this case the safety value H f factor is exceeded and various side effects can also appear. As a result, lowering the dose levels, below their intrinsic toxicity levels and enhancing the heating capabilities of MNPs have become the major goals for the scientific community involved in magnetic hyperthermia research. Several theoretical models were developed in order to understand the basic mechanisms and.