Perhaps this may sound like an overstatement to some, but nanomaterials are drastically changing the way we live and work, giving birth to some of the most mind-boggling applications and technologies the world has ever seen.
The properties of many conventional materials change dramatically when ‘shrank’ to 100 nanometers or less. At that level, a nanoparticle (NP) has a high surface-area-to-volume ratio, which gives it a multitude of interesting size-dependent properties, governed in part by the laws of quantum physics and chemistry.
In the last years, various nanotechnologies have taken advantage of these properties, giving rise to incredible innovations in industries such as agriculture, automotive, construction, electronics, environment, renewable energies and others.
Nanotechnology in cancer treatment
In nanomedicine, the functionalisation of certain NPs, meaning the introduction of ‘biologically friendly’ organic molecules or polymers onto their surface, has led to revolutionary applications such as drug delivery, therapy and diagnostic techniques, anti-microbial approaches and cellular repair know-how, the latter by the so-called ‘nanorobots’, which take advantage of the NP’s optical, thermal, electromagnetic and nuclear properties .
One of the most devastating illnesses successfully tackled today in medicine is cancer. Nanotechnology has made it possible to significantly advance the detection, treatment and cure of many oncological diseases thought to be without any treatment not so long ago.
The research and development (R&D) of NPs for use in oncological disease detection and therapy has shown great progress over the past 20 years. NPs have been employed as contrast enhancement agents for imaging, drug delivery vehicles, and, most recently, as a therapeutic component in initiating tumor cell death in magnetic and photonic ablation therapies.
The so-called magnetic nanoparticles (MNPs), with appropriate polymer or lipid coating shells, are some of the most widely used NPs (granular systems) , due to their strong temperature and size-dependent magnetic properties . The presence of a coating shell on the surface of MNPs promotes favorable interactions between the MNPs and the biological system, being needed in order to stabilise the MNPs in the colloid during their maintenance .
Fighting cancer with magnetic nanoparticles
The correct introduction of MNPs into the body is crucial for any successful medical application. Physicochemical properties of MNPs such as size, shape, surface charge, and hydrophobicity need to be greatly modulated in order to evade the body’s immune system and undergo successful endocytosis (‘bring-into-cell’) process [5-7]. This can be achieved by means of active and passive targeting.
As soon as the MNPs are injected into the blood circulatory system, they are subjected mainly to the action of the macrophages . The principal goal of the macrophage cells is to clear any exogenous element from the body. In order to do this, they capture any invading entity and concentrate it in areas with high macrophage activity. This phenomenon gives rise to a passive targeting of MNPs to areas with high macrophage activity (i.e. liver or infected areas).
The preferential accumulation of MNPs inside tumors is achieved by exploiting their intrinsic physicochemical properties and the enhanced permeability and retention (EPR) effect, investigated for the first time in 1986, by Maeda and Matsumura, for targeting metastatic solid tumors.
The probability of redirecting the MNPs to the desired target tissues can be enhanced by labeling their surface with ligands that specifically bind to surface receptors on target cells. Although this approach has been proposed around 40 years ago, ligand-decorated MNPs have only recently paved their way to clinical test trials This kind of targeting is called active targeting. In addition, MNPs can be directed to desired areas through magnetic gradients .
MNPs can be used as heat sources in magnetic hyperthermia (MHT), a novel, cutting-edge cancer treatment therapy [10,11]. When MNPs are subjected to an external, high-frequency magnetic field, they absorb energy from this field, which is converted into heat (the magnetisation of MNPs follows an open loop hysteresis cycle). This heat then acts on the tissues surrounding the nanoparticles and eventually kills the tumor cells. Furthermore, in this same process, personalised medicine (attached to MNPs through adequate linkers) can be directly released into the cancer cells, once the MNPs are in the right place .
There are several techniques used to detect and map the position of MNPs inside the body. Since MNPs can be targeted to specific cells, they can be used as tracers for specific diseases. According to the Langevin curve, MNPs tend to saturate (i.e., reach the same polarisation of the magnetic moments) faster than other materials present in biological systems. This rapid saturation causes nonlinearities in the magnetic response, which can be used to detect the presence of MNPs .
Furthermore, based on this principle, the spatial distribution of magnetic nanoparticles is obtained by means of magnetic particle imaging (MPI) , an emerging non-invasive tomographic technique that directly detects superparamagnetic nanoparticle tracers. Finally, MNPs can be used as contrast agents in magnetic resonance imaging (MRI), due to the distortions in the T1 and T2 relaxation times, caused by the magnetic moment of the particles .
The MRI contrast in soft tissues is given by differences in the proton density, spin-lattice relaxation time (T1) and spin-spin relaxation time (T2) of the hydrogen protons. MRI has become one of the most widely used and powerful tools for non-invasive clinical diagnosis, due to its high soft-tissue contrast, spatial resolution, and penetration depth 
Theragnostic MNPs (magnetite, Fe3O4 and maghemite, Fe2O3, NPs) possess great potential for image-guided cancer therapies, being also naturally present in the body (e.g., ferritin, hemosiderin, transferrin, hemoglobin).
Functionalised superparamagnetic iron oxide nanoparticles
Superparamagnetic iron oxide nanoparticles (SPIONs) are one of the best candidates for combined and personalised detection and treatment of cancers, thanks to their unique properties (like physical and chemical stability, natural abundance and environmental friendliness).
Coating the SPIONs surfaces with various chemical compounds, macromolecules or NPs, such as small molecules (e.g., oleic acid, alkyl phosphonates, carboxylates etc.) , polymers (e.g., dextran, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyethyleneimine (PEI), chitosan, dendrimers etc.)  and inorganic materials (e.g., gold, silver, silica etc.)  allows for (further) surface functionalisation of these nanomaterials, providing high colloidal stability and preventing aggregations and/or agglomerations.
This functionalisation prevents the formation of a protein corona on the surfaces of the NPs  and allows for improved biocompatibility, protection against macrophage cells and prolongated blood circulation time. Compared with inorganic coating materials such as silica, polymers provide better biocompatibility and biodegradability.
The polymer coatings of SPIONs can be loaded with various therapeutic agents in order to facilitate MRI-guided drug delivery, gene delivery, photothermal therapy (PTT), photodynamic therapy (PDT) or MHT. Cancer specificity can be further increased by using different ‘smart’ polymers, for controlled drug release in response to external stimuli such as pH, temperature or tumor enzymes.
Although some SPION formulations have been approved by the United States Food and Drug Administration, FDA (e.g., Feraheme® and Feridex I.V.®), no single functionalised SPION has ever been approved for use in patients to this date. This might be caused, in part, by ‘the publish or perish’ pressure from the academic environment, where R&D of ever new SPIONs is rewarded with high-impact scientific publications and/or related academic rewards, whereas the ‘real life’ clinical development of existing formulations is considered ‘not so exciting’ and, consequently, less important to pursue, from this point of view.
Most probably, however, the great financial and economic risks posed by their large-scale commercialisation and/or the great competitiveness among the various currently-available anti-cancer medical solutions might be the real reason behind their absence from the respective markets.
The impact of a variety of parameters (such as biocompatibility, colloidal stability and biodegradability) on human biological responses must be comprehensively understood and tested before promising products can be further developed. In the case of ‘activatable’ SPIONs, the prodrug and the cleaved products need to be studied. In addition, potential toxic side-effects of added components (such as Au and PPy) should be more carefully examined.
Another major challenge in translational research is the feasibility and consistency to produce multifunctional SPIONs industrially, on a large scale. The standardisation and scalability of SPIONs remain concerns for clinical development and commercialisation .
The future of medicine is Nano
Despite all these challenges, next-generation SPIONs still hold great potential for personalised medicine. Besides organic and/or inorganic hybrid SPIONs, other NPs (e.g., pure organic NPs) are also intensively used for cancer theragnostics (including drug delivery, PTT, PDT, fluorescence imaging and photoacoustic imaging), which inspires even more interest in future R&D in this area (hopefully more towards clinical trials and large-scale commercialisation) .
Intense interdisciplinary R&D, crossing nanotechnology, materials sciences, cancer biology and clinical medicine, together with a focus on clinical translation, will ultimately lead to tangible benefits for cancer patients.
Nanotechnology is already helping to expand the knowledge, medical tools and therapies currently available to doctors. Therefore, the nanotechnology products market, represented by medical and healthcare applications, is expected to increase considerably in the next years.
MNPs are strong candidates for diagnostics and drug delivery in medicine. They can be simply functionalised for specific applications benefiting from their response to external magnetic fields.
SPIONs are considered as some of the most promising nanomaterials for simultaneous MRI contrast enhancement and drug delivery for cancers that are traditionally treated with a combination of surgical resection, radiation therapy, and chemotherapy.
Even if nanomedicine techniques are yet to be found in every hospital in the world and raise a lot of complex economic and ethical issues (which need to be addressed carefully), it is obvious that the impact of nanotechnology on the evolution of medicine and the quality of life is a positive one and cannot be ignored.
“Being aware of today’s new materials and their technologies is as important as being bilingual. Everybody should have at least a general idea about the present revolution in materials science and technology, as it slowly reshapes the world we are living in.”
Materials and Processes Specialist
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