Introduction: Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death. Methods: The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice. Results: All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H = 15.4 kA/m, f = 435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced. Conclusion: The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.

Many different nanostructures have been developed for biomedical applications to date. Among them, iron oxide nanoparticles have been very prominent in MRI in diagnostic radiology. Nowadays, nanoparticle-based therapeutic applications have gained increased interest, leading to the development of a great variety of different and, in parts, sophisticated nanoparticle formulations. Whereas nanotherapy has been confined to the preclinical phase, magnetic hyperthermia has entered into the clinical phase via controlled studies in patients. Owing to the versatility of nanoparticles, researchers envision the combination of multiple modalities (e.g., targeting, diagnostics and therapy) to one carrier. Nevertheless, such approaches have been challenging due to the necessity of the adaptation of at least partially counteracting parameters between the different modalities, which will be analyzed in this review.

Magnetic nanoparticles are promising tools for the minimal invasive elimination of small tumours in the breast using magnetically-induced heating. The approach complies with the increasing demand for breast conserving therapies and has the advantage of offering a selective and refined tuning of the degree of energy deposition allowing an adequate temperature control at the target. The biophysical basis of the approach, the magnetic and structural properties of magnetic nanoparticles are reviewed. Results with model targets and in vivo experiments in laboratory animals are reported.

Purpose Tumor 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. Methods Superparamagnetic 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. Results Exceptionally high SAR values ranging from 658 ± 53 W*g_Fe ⁻¹ for OD15 up to 900 ± 22 W*g_Fe ⁻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. Conclusions Concluding, the studied magnetic nanoparticles lead to extensive cell death in human tumor xenografts and are considered suitable platforms for future hyperthermic studies.

Au@Fe3O4 Janus particles (JPs) are heteroparticles with discrete domains defined by different materials. Their tunable composition and morphology confer multimodal and versatile capabilities for use as contrast agents and drug carriers in future medicine. Au@Fe3O4 JPs have colloidal properties and surface characteristics leading to interactions with proteins in biological fluids. The resulting protein adsorption layer ("protein corona") critically affects their interaction with living matter. Although Au@Fe3O4 JPs displayed good biocompatibility in a standardized in vitro situation, an in-depth characterization of the protein corona is of prime importance to unravel underlying mechanisms affecting their pathophysiology and biodistribution in vitro and in vivo. Here, we comparatively analyzed the human plasma corona of Au-thiol@Fe3O4-SiO2-PEG JPs (NH2-functionalized and non-functionalized) and spherical magnetite (Fe3O4-SiO2-PEG) particles and investigated its effects on colloidal stability, biocompatibility and cellular uptake. Label-free quantitative proteomic analyses revealed that complex coronas including almost 180 different proteins were formed within only one minute. Remarkably, in contrast to spherical magnetite particles with surface NH2 groups, the Janus structure prevented aggregation and the adhesion of opsonins. This resulted in an enhanced biocompatibility of corona sheathed JPs compared to spherical magnetite particles and corona-free JPs.