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Progress in the design of nanoscale magnets for localized hyperthermia cancer therapy has been largely driven by trial-and-error approaches, for instance, by changing of the stoichiometry composition, size, and shape of the magnetic entities. So far, widely different and often conflicting heat dissipation results have been reported, particularly as a function of the nanoparticle concentration. Thus, achieving hyperthermia-efficient magnetic ferrofluids remains an outstanding challenge. Here we demonstrate that diverging heat-dissipation patterns found in the literature can be actually described by a single picture accounting for both the intrinsic magnetic features of the particles (anisotropy, magnetization) and experimental conditions (concentration, magnetic field). Importantly, this general magnetic-hyperthermia scenario also predicts a novel non-monotonic concentration dependence with optimum heating features, which we experimentally confirmed in iron oxide nanoparticle ferrofluids by fine-tuning the particle size. Overall, our approach implies a magnetic hyperthermia trilemma that may constitute a simple strategy for development of magnetic nanomaterials for optimal hyperthermia efficiency.

Iron oxide nanoparticles have found an increasing number of biomedical applications as sensing or trapping platforms and therapeutic and/or diagnostic agents. Most of these applications are based on their magnetic properties, which may vary depending on the nanoparticle aggregation state and/or concentration. In this work, we assess the effect of the inter- and intra-aggregate magnetic dipolar interactions on the heat dissipation power and AC hysteresis loops upon increasing the nanoparticle concentration and the hydrodynamic aggregate size. We observe different effects produced by inter- (long distance) and intra-aggregate (short distance) interactions, resulting in magnetizing and demagnetizing effects, respectively. Consequently, the heat dissipation power under alternating magnetic fields strongly reflects such different interacting phenomena. The intra-aggregate interaction results were successfully modeled by numerical simulations. A better understanding of magnetic dipolar interactions is mandatory for achieving a reliable magnetic hyperthermia response when nanoparticles are located into biological matrices.

PurposeTumor cells can be effectively inactivated by heating mediated by magnetic nanoparticles. However, optimized nanomaterials to supply thermal stress inside the tumor remain to be identified. The present study investigates the therapeutic effects of magnetic hyperthermia induced by superparamagnetic iron oxide nanoparticles on breast (MDA-MB-231) and pancreatic cancer (BxPC-3) xenografts in mice in vivo.MethodsSuperparamagnetic iron oxide nanoparticles, synthesized either via an aqueous (MF66; average core size 12 nm) or an organic route (OD15; average core size 15 nm) are analyzed in terms of their specific absorption rate (SAR), cell uptake and their effectivity in in vivo hyperthermia treatment.ResultsExceptionally high SAR values ranging from 658 ± 53 W*gFe−1 for OD15 up to 900 ± 22 W*gFe−1 for MF66 were determined in an alternating magnetic field (AMF, H = 15.4 kA*m−1 (19 mT), f = 435 kHz). Conversion of SAR values into system-independent intrinsic loss power (ILP, 6.4 ± 0.5 nH*m2*kg−1 (OD15) and 8.7 ± 0.2 nH*m2*kg−1 (MF66)) confirmed the markedly high heating potential compared to recently published data. Magnetic hyperthermia after intratumoral nanoparticle injection results in dramatically reduced tumor volume in both cancer models, although the applied temperature dosages measured as CEM43T90 (cumulative equivalent minutes at 43°C) are only between 1 and 24 min. Histological analysis of magnetic hyperthermia treated tumor tissue exhibit alterations in cell viability (apoptosis and necrosis) and show a decreased cell proliferation.ConclusionsConcluding, the studied magnetic nanoparticles lead to extensive cell death in human tumor xenografts and are considered suitable platforms for future hyperthermic studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-014-1417-0) contains supplementary material, which is available to authorized users.

Magnetic nanoparticles, and in particular iron oxide nanoparticles (mainly magnetite and maghemite), are being widely used in the form of aqueous colloids for biomedical applications. In such colloids, nanoparticles tend to form assemblies, either aggregates, if the union is permanent, or agglomerates, if it is reversible. These clustering processes have a strong impact

Although iron oxide magnetic nanoparticles (MNP) have been proposed for numerous biomedical applications, little is known about their biotransformation and long-term toxicity in the body. Dimercaptosuccinic acid (DMSA)-coated magnetic nanoparticles have been proven efficient for in vivo drug delivery, but these results must nonetheless be sustained by comprehensive studies of long-term distribution, degradation and toxicity. We studied DMSA-coated magnetic nanoparticles effects in vitro on NCTC 1469 nonparenchymal hepatocytes, and analyzed their biodistribution and biotransformation in vivo in C57BL/6 mice. Our results indicate that DMSA-coated magnetic nanoparticles have little effect on cell viability, oxidative stress, cell cycle or apoptosis on NCTC 1469 cells in vitro. In vivo distribution and transformation was studied by alternating current magnetic susceptibility measurements, a technique that permits distinction of MNP from other iron species. Our results show that DMSA-coated MNP accumulate in spleen, liver and lung tissues for extended periods of time, in which nanoparticles undergo a process of conversion from superparamagnetic iron oxide nanoparticles to other nonsuperparamagnetic iron forms, with no significant signs of toxicity.

In the pursuit of controlling the heat exposure mediated by magnetic nanoparticles, we provide new guidelines for tailoring magnetic relaxation processes via dipolar interactions. For this purpose, highly crystalline and monodisperse magnetic iron oxide nanocrystals whose sizes range from 7 to 22 nm were synthesized by thermal decomposition of iron organic precursors in 1-octadecene. The as-synthesized nanoparticles are soft nanomagnets, showing superparamagnetic-like behavior and SAR values which progressively increase with particle size, field frequency, and amplitude up to 3.6 kW/g Fe . Our data show the influence of media viscosity, particle size, and concentration on dipolar interactions and consequently on the magnetic relaxation processes related to the heat release. Understanding the role of dipolar interactions is of great importance toward the use of iron oxide nanoparticles as efficient hyperthermia mediators.

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