Magnetic nanoparticles in regenerative medicine: what of their fate and impact in stem cells?
Graphical abstract
Introduction
Nanotechnology holds the potential to transform the field of medicine by permitting the development of combined and remote theranostic applications. To this effect, investigations into multiple nanoparticle configurations have been the subject of intensive research, each of which can be readily interfaced with living cells due to their size compatibility, and each possessing exploitable and unique therapeutic properties [1]. Naturally, over 200 nanotechnology-enabled products have already undergone full clinical trials, and the field keeps expanding. Tailored treatments, such as a patient-specific targeted drug release that minimizes systemic toxicity, have become the current focus of nanoparticle-based therapy.
Within this field of research, magnetic nanoparticles are featured prominently in the development of new diagnostic and therapeutic methodologies, where they pose an exciting prospect due to their inherent properties [2,3]. For instance, their ability to generate a local magnetic field makes them relevant as magnetic resonance imaging (MRI) contrast agents [4]. Due to their strong magnetization values, they have been mainly studied as T2 contrast agents, but recent efforts have focused on improving their use as T1 contrast agents while further increasing T2 contrast [[5], [6], [7], [8], [9]]. Magnetic-activated cell sorting (MACS) also uses superparamagnetic nanoparticles with specific targeting antibodies [10] as a standard procedure for the sorting of cell populations, with applications in cancer, stem cell and immunology research, among others [11]. With the advent of microfluidic integration [[12], [13], [14]], magnetic cell sorting has become highly relevant in the field of cancer clinical diagnostics, where it is used and studied for capturing and sorting of circulating tumor cells [[15], [16], [17], [18]]. Magnetic nanoparticles have also been used for cancer therapy via magnetic hyperthermia, or heat generation after exposure to an alternating magnetic field, that is currently under clinical trials for the treatment of prostate carcinoma [19,20] and glioblastoma [21,22]. Recent efforts have focused on the optimization of the heating efficiency by producing new designs [23], such as nanocubes [24] or multicore nanoparticles [25]. Photothermal therapy, a second hyperthermal modality with higher heat generation potential per nanoparticle, has also emerged [[26], [27], [28]].
Recently, the regenerative medicine and tissue engineering fields have found a surge of interest in magnetic nanoparticles, using their magnetomechanical potential as an innovative approach to spatially organize [[29], [30], [31]] and stimulate [32] stem cells. Magnetomechanical forces have for example been used for stem cell differentiation into the chondrogenic [33,34], adipogenic [35] or mesodermal cardiac pathways [36]. In most of these applications, the necessary step to endow the cells with the pursued theranostic properties consists in the internalization of magnetic nanoparticles in their intracellular environment. It should be noted first that nanoparticle internalization does not impair the cellular magnetic force generated, being directly the sum of the magnetic moment of each nanoparticle independently of its location, an essential feature in cell targeting, drug delivery, and tissue engineering applications. What remains to be explored extensively then are the ultimate fate and biotransformations that nanoparticles undergo after cellular uptake and endosomal confinement. Importantly, for most theranostic applications the typically used nanoparticles are iron oxide-based [37], and iron is a naturally occurring bio-element with its own metabolic pathway in mammals. In the organism, it has been described that iron oxide nanoparticles injected intravenously are internalized, mostly in macrophages, then join the iron pool and integrate into the natural iron metabolic pathway. Conversely, the degradation of iron oxide nanoparticles may transform iron oxide into unbound iron ions, which can trigger the generation of reactive oxygen species via the Fenton reaction, leading to oxidative stress and subsequent cell damage [38].
Anti-cancer therapies take advantage of these features by targeting the iron metabolism [39], with the ultimate induction of cell death through ferroptosis [40]. In contrast to this, for regenerative medicine applications, any cell damage must be avoided. The relationship between degradation of magnetic nanoparticles and cellular cytotoxicity is not quite clear yet, or at least has not been directly demonstrated. Besides, it is important to highlight that the biodegradation of magnetic nanoparticles may not only severely impact their long-term stability, it may also decrease their magnetic moment and thus their theranostic potential. Indeed, as shown previously in a stem cell-tissue model, long-term nanoparticle degradation translates into a marked decrease of cell magnetization [41]. Strategies to prevent nanoparticle degradation should then be envisaged to maximize long-term theranostic potential and possibly avoid any source of toxicity. For instance, fine tuning of a gold shell [42,43] or a polymeric coating [44] could shield the nanoparticles from degradation and maintain their integrity and magnetic properties.
Given the upsurge of interest for magnetic nanoparticles in the regenerative medicine field and the challenges imposed by their degradation on their potential cytotoxicity as well as their theranostic applicability, this review will focus on the interplay of these three topics. First, it will summarize the potential of magnetic nanoparticles for regenerative medicine applications, using mostly stem cells as the basis of regeneration, including imaging of stem cell grafts, magnetic stem cell targeting, and tissue engineering, among others. Then, discussion will shift to the impact magnetic nanoparticles may have on the differentiation of stem cells, keeping in mind that differentiation processes take weeks and are an indicator of long-term toxicity. Finally, this review will assess a potential correlation between long-term toxicity, intracellular transformations of the nanoparticles, and the alteration in the expression of genes related to iron metabolism. The aim is to draw up the most comprehensive inventory of the reported quantified changes in cellular iron metabolism with time.
Section snippets
Magnetic nanoparticles for cell-based therapies and regenerative medicine
Magnetic nanoparticles have a direct applicative potential in biomedicine (Fig. 1). They were first developed as contrast agents for MRI, and their range of applications keeps expanding. The number of clinical trials and the increasing amount of products approved by regulatory boards indicate this growing interest. Treatments already at disposition in the clinic include MRI contrast agents for liver lesions (Resovist®) or sentinel node detection (Sienna+®), treatment of brain tumors via
Synthesis of magnetic nanoparticles
Numerous chemical methods can be used to synthesize magnetic nanoparticles: coprecipitation of iron salts [[114], [115], [116], [117]], sol-gel synthesis [118] including microwave assisted ones [119], hydrothermal reactions [120], hydrolysis and thermolysis of precursors [121], synthesis in microemulsions [122], flow injection synthesis [123], electrospray synthesis [124] and microfluidic flow synthesis [[125], [126], [127], [128], [129]]. In this review, we will only cover very briefly the
Degradation of magnetic nanoparticles internalized in cells
The first step for most biomedical applications involving magnetic nanoparticles is to internalize them inside the cells, where they are to be left within. Consequently, one mandatory prerequisite prior to clinical translation is to explore their long-term intracellular fate and understand whether they behave as a single indissoluble unit or if they can, on the contrary, be affected by the surrounding biological environment. Primary concerns associated with a possible biodegradation would be
Interplay between nanoparticles degradation, stem cell function, and iron metabolism
Despite the acceptance and popularity of the applicative potential of magnetic nanoparticles in medicine, we must still resolve any issues regarding their impact and fate upon internalization within cells. The answer to this remaining question is not straightforward. Studies comparing several factors two-by-two exist, but a larger study that correlates the dose of internalized nanoparticles, degradation rate, impact of the differentiation pathway and the modulation of expression of iron
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by the European Research Council (ERC-2014-CoG project MaTissE #648779).
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