**5. Concluding remarks**

Due to the multiple applications of M-IONPs in biomedical fields (drug delivery, as contrast agents, hyperthermia treatment), it was also verified the effects of the hollow nanoparticles

As mentioned in the previous section, M-IONPs mediate DNA lesions in normal cells, and this property is also exerted in the case of tumor cells. The effect observed was dose-dependent and time-dependent and consisted of damage of tail length and DNA strand breaks. The results were similar in all the tumor cell lines tested: human breast cancer cell line (MCF-7),

Another mechanism of M-IONPs by which are able to harm cancer cells is represented by the ability to induce magnetic hyperthermia in the form of heat generated by the release of energy after applying a high-frequency alternating magnetic field. The principle of action of this technique consists in raising the cell temperature abnormally to 41–45°C, which leads to significant detrimental effects that can be reversible in the case of normal cells whereas irre-

A novel proposed mechanism for M-IONPs-induced cell death is enucleation described by Paunescu and coworkers, process observed after exposure of breast cancer cells (MCF-7) and human melanoma (SK-BR-3) to magnetic iron oxide nanoparticles obtained by combustion synthesis [106]. The enucleation phenomena is well described for erythroid terminal differentiation process and there is also used a term in the literature "enucleation sign" that is specific for enhanced computed tomographic images of the ruptured hepatocellular carcinoma. The definition for this term is "the separation of tumor content with intraperitoneal rupture into the perihepatic space, which is seen as low attenuating lesion from peripheral enhancing rim on arterial phase imaging" [107]. The process observed by Paunescu et al. was described as a non-physiological process and it was unrelated with the process described for erythroblast

The M-IONPs proved a cytotoxic effect against murine melanoma cells B16, cytotoxicity eval-

Other mechanisms of action as anticancer agents may be attributed to M-IONPs, mechanisms that are related with the effects induced by the chemotherapeutical agents loaded in the engineered nanoparticles. The large surface-to-volume ratio characteristic for M-IONPs make them suitable to adsorb proteins or load drugs and attractive for *in vivo* applications, such as MRI, drug and gene delivery, cancer treatment, hard tissue repair and tissue engineering and

Recent studies mention the use of M-IONPs as improved contrast agents in the diagnosis of cardiovascular pathologies, mainly in atherosclerosis for detection of unstable plaques by the means of MRI (magnetic resonance imaging) [104]. The commercial products based on M-IONPs applied as contrast agents in MRI are: Ferumoxytol (Feraheme—detection of primary tumors and cancer lymph node metastasis), Ferumoxides (Feridex—detection of liver lesions), Ferucarbotran (Resovist—detection of small focal liver lesions), Ferumoxtran—10 (Combidex or Sinerem—detection of metastatic disease in lymph nodes), etc. [104]. Some of these products are included in clinical trials for additional effects, such as Endorem for tracking monocytes and inflammation cells, Feridex—to keep track of adult bone

human fibrosarcoma cells, lung cancer and cervix carcinoma cells [103].

(without payload) on different tumor cell lines.

uated by the means of MTT viability assay [108].

versible for cancer cells [105].

246 Iron Ores and Iron Oxide Materials

enucleation [106].

biosensors [105].

The intrinsic magnetic properties, the biocompatibility and biodegradability and the capacity to respond to an external magnetic field are unique features that recommend magnetic iron oxide nanoparticles as promising nanomaterials in biomedical applications. The recent advances in this field led to the synthesis of engineered and targeted M-IONPs that might be successfully applied for smart therapies, including controlled drug release, hyperthermia treatment, magnetofection and gene delivery, mapping of lymph nodes and tissue engineering. M-IONPs could be considered theranostics tools based on their capacity to combine their use in diagnostic, treatment and follow-up of a pathology. Despite all these beneficial effects, an important matter should be taken into consideration when M-IONPs are administered *in vivo*, this matter consisting in the thorough analysis of the factors that might induce toxic reactions like size, charge, coating agent, functional groups and shape. There are still some challenges to achieve M-IONPs optimum efficacy and safety, but the existent drawbacks can be corrected by the improvement of their properties by the means of appropriate methods, further studies and inclusion in clinical trials.
