No abstract

Metastasis is the predominant cause of cancer deaths due to solid organ malignancies; however, anticancer drugs are not effective in treating metastatic cancer. Here we report a nanotherapeutic approach that combines magnetic nanocluster-based hyperthermia and free radical generation with an immune checkpoint blockade (ICB) for effective suppression of both primary and secondary tumors. We attached 2,2′-azobis(2-midinopropane) dihydrochloride (AAPH) molecules to magnetic iron oxide nanoclusters (IONCs) to form an IONC−AAPH nanoplatform. The IONC can generate a high level of localized heat under an alternating magnetic field (AMF), which decomposes the AAPH on the cluster surface and produces a large number of carbon-centered free radicals. A combination of localized heating and free radicals can effectively kill tumor cells under both normoxic and hypoxic conditions. The tumor cell death caused by the combination of magnetic heating and free radicals led to the release or exposure of various damage-associated molecule patterns, which promoted the maturation of dendritic cells. Treating the tumor-bearing mice with IONC−AAPH under AMF not only eradicated the tumors but also generated systemic antitumor immune responses. The combination of IONC−AAPH under AMF with anti-PD-1 ICB dramatically suppressed the growth of untreated distant tumors and induced long-term immune memory. This IONC−AAPH based magneto-immunotherapy has the potential to effectively combat metastasis and control cancer recurrence.

Magnetic iron oxide nanoparticles (MIONs) can generate heat under an alternating magnetic field, enabling a wide range of applications from water treatment to cancer hyperthermia therapy. For most magnetic heating applications, it is crucial to generate a high level of heat with a low dose of MIONs. Current methods to increase the specific absorption rate (SAR) of MIONs include increasing their size and doping iron oxide nanocrystals with other metal elements. Here, we demonstrate that controlled oxidation and surface modification can significantly increase SAR of MIONs. We synthesized MIONs of different core sizes and with different coatings, including phospholipid-PEG and triethylenetetramine (TETA). We oxidized PEG-coated MIONs in a controlled fashion and measured the SAR values of the MIONs under different oxidation states. We found that, with controlled oxidation, the SAR values of 15-nm and 18-nm MIONs increased by ∼1.87 fold after two weeks of oxidation. A similar fold-increase in SAR was achieved for 15-nm MIONs with TETA coating compared with PEG coating. We systematically characterized the physical properties of MIONs and showed that oxidation caused MIONs to transition from magnetite to maghemite, resulting in increased anisotropy constant and SAR values. Our results demonstrate new approaches to significantly increase the heating capacity of MIONs by controlled nanocrystal oxidation and surface modification.

Objective. We present a combination of a power electronics system and magnetic nanoparticles that enable frequency-multiplexed magnetothermal-neurostimulation with rapid channel switching between three independent channels spanning a wide frequency range. Approach. The electronics system generates alternating magnetic field spanning 50 kHz to 5 MHz in the same coil by combining silicon (Si) and gallium-nitride (GaN) transistors to resolve the high spread of coil impedance and current required throughout the wide bandwidth. The system drives a liquid-cooled field coil via capacitor banks, forming three series resonance channels which are multiplexed using high-voltage contactors. We characterized the system by the output channels’ frequencies, field strength, and switching time, as well as the system’s overall operation stability. Using different frequency–amplitude combinations of the magnetic field to target specific magnetic nanoparticles with different coercivity, we demonstrate actuation of iron oxide nanoparticles in all three channels, including a novel nanoparticle composition responding to magnetic fields in the megahertz range. Main results. The system achieved the desired target field strengths for three frequency channels, with switching speed between channels on the order of milliseconds. Specific absorption rate measurements and infrared thermal imaging performed with three types of magnetic nanoparticles demonstrated selective heating and validated the system’s intended use. Significance. The system uses a hybrid of Si and GaN transistors in bridge configuration instead of conventional amplifier circuit concepts to drive the magnetic field coil and contactors for fast switching between different capacitor banks. Series-resonance circuits ensure a high output quality while keeping the system efficient. This approach could significantly improve the speed and flexibility of frequency-multiplexed nanoparticle actuation, such as magnetogenetic neurostimulation, and thus provide the technical means for selective stimulation below the magnetic field’s fundamental spatial focality limits.

Stem cell therapy represents one of the most promising approaches for tissue repair and regeneration. However, the full potential of stem cell therapy remains to be realized. One major challenge is the insufficient homing and retention of stem cells at the desired sites after in vivo delivery. Here, we provide a proof-of-principle demonstration of magnetic targeting and retention of human muscle-derived stem cells (hMDSCs) in vitro through magnetic force-mediated internalization of magnetic iron oxide nanoparticles (MIONs) and the use of a micropatterned magnet. We found that the magnetic force-mediated cellular uptake of MIONs occurs through an endocytic pathway, and the MIONs were exclusively localized in the lysosomes. The intracellular MIONs had no detrimental effect on the proliferation of hMDSCs or their multilineage differentiation, and no MIONs were translocated to other cells in a coculture system. Using hMDSCs and three other cell types including human umbilical vein endothelial cells (HUVECs), human dermal fibroblasts (HDFs), and HeLa cells, we further discovered that the magnetic force-mediated MION uptake increased with MION size and decreased with cell membrane tension. We found that the cellular uptake rate was initially increased with MION concentration in solution and approached saturation. These findings provide important insight and guidance for magnetic targeting of stem cells in therapeutic applications.