The interest in hybrid nanoparticles for various applications in biomedicine is growing inevitably, stimulating research towards not only more effective, but also more accessible systems. This resulted in the emergence of advanced synthetic protocols with optimized conditions for the production of nanoparticles with high yields and desired morphologies, which ultimately determine their physicochemical and biomedical properties. While these challenges were sufficient for scientists a few decades ago, the sustainability of the synthetic methods is now an important aspect. From this perspective, nanoparticle production methods based on physical principles, such as spark discharge phenomena, could provide an interesting alternative to labor-intensive and environmentally harmful chemical synthesis. The benefits of clean and sustainable physical production routes for various nanomaterials are already recognized in the fields of catalysis and electronics. Biomedicine on the other hand has been reluctant to embrace the new methodologies, as they do not inherently provide nanoparticles dispersed in aqueous media, which is essential for their safe administration and reliable physiological performance. In this work, we investigated the potential of spark discharge as an alternative method to produce hybrid palladium/iron oxide nanoparticles intended for cancer thermo-brachytherapy by leveraging the magnetothermal properties of iron and the favorable radioactive features of the palladium radioisotope. Focusing on the aqueous harvesting of the nanoparticles produced in VSParticle’s spark discharge generator, we determined the optimal settings compatible with the connected bubbling column and identified the pitfalls and possible solutions to the intrinsic challenges, such as low yields and aggregation.

Objective: To investigate the potential of hybrid Pd/Fe-oxide magnetic nanoparticles designed for thermo-brachytherapy of breast cancer, considering their specific loss power (SLP) and clinical constraints in the applied magnetic field. Methods: Hybrid nanoparticles consisting of palladium-core and iron oxide shell of increasing thickness, were suspended in water and their SLPs were measured at varying magnetic fields (12–26 mT peak) and frequencies (50–730 kHz) with a commercial alternating magnetic field generator (magneTherm™ Digital, nanoTherics Ltd.). Results: Validation of the heating device used in this study with commercial HyperMag-C nanoparticles showed a small deviation (±4%) over a period of 1 year, confirming the reliability of the method. The integration of dual thermometers, one in the center and one at the bottom of the sample vial, allowed monitoring of homogeneity of the sample suspensions. SLPs measurements on a series of nanoparticles of increasing sizes showed the highest heating for the diameter of 21 nm (SLP = 225 W/g) at the applied frequencies of 346 and 730 kHz. No heating was observed for the nanoparticles with the size <14 nm, confirming the importance of the size-parameter. The heating ability of the best performing Pd/Fe-oxide-21 was calculated to be sufficient to ablate tumors with a radius ±4 and 12 mm using 10 and 1 mg/mL nanoparticle concentration, respectively. Conclusions: Nanoparticles consisting of non-magnetic palladium-core and magnetic iron oxide shell are suitable for magnetic hyperthermia/thermal ablation under clinically safe conditions of 346 kHz and 19.1 mT, with minimal eddy current effects in combination with maximum SLP.

Multifunctional, biocompatible magnetic materials, such as iron oxide nanoparticles (IONPs), hold great potential for biomedical applications including diagnostics (e.g., MRI) and cancer therapy. In particular, they can play a crucial role in advancing cancer thermotherapy by generating heat when administered intratumorally and when exposed to an alternating magnetic field. This heat application is often combined with radio- (chemo)therapy and/or imaging. Consequently, the design of materials for such a multimodal approach requires hybrid nanoparticles that retain their magnetic properties while integrating additional functionalities. This work introduces synthesis and investigation of magnetically enhanced nanoparticles with a palladium core (envisioned for future radiolabeling with therapeutic 103Pd) and a magnetic iron oxide shell containing paramagnetic manganese (Pd/Fe|(nMn)-oxide, n = 0.25 and 0.5). Doping the iron oxide lattice with Mn significantly increases magnetic saturation, boosting specific loss power up to 1.7 times compared to that of undoped analogs. Interestingly, higher Mn-content in Pd/Fe|(0.5Mn)-oxide leads to a pronounced Mn outer rim, enhancing the heating efficiency at 346 kHz and 23 mT and contributing to the water exchange on the surface of the paramagnetically doped nanoparticles, resulting in additional T1 MRI contrast. The enhanced magnetic properties of the hybrid Pd/Fe|Mn-oxide nanoparticles enable effective therapeutic outcomes with injection of only small quantities of the material, offering great potential for effective cancer treatment strategies that combine hyperthermia/thermal ablation with radiotherapy while allowing for real-time monitoring via MRI.

While hyperthermia has been shown to induce a variety of cytotoxic and sensitizing effects on cancer tissues, the thermal dose–effect relationship is still not well quantified, and it is still unclear how it can be optimally combined with other treatment modalities. Additionally, it is speculated that different methods of applying hyperthermia, such as water bath heating or electromagnetic energy, may have an effect on the resulting biological mechanisms involved in cell death or in sensitizing tumor cells to other oncological treatments. In order to further quantify and characterize hyperthermia treatments on a cellular level, in vitro experiments shifted towards the use of 3D cell spheroids. These are in fact considered a more representative model of the cell environment when compared to 2D cell cultures. In order to perform radiofrequency (RF)-induced heating in vitro, we have recently developed a dedicated electromagnetic field applicator. In this study, using this applicator, we designed and validated an experimental setup which can heat 3D cell spheroids in a conical polypropylene vial, thus providing a reliable instrument for investigating hyperthermia effects at the cellular scale.

Background: Treatment of early-stage breast cancer currently includes surgical removal of the tumor and (partial) breast irradiation of the tumor site performed at fractionated dose. Although highly effective, this treatment is exhaustive for both patient and clinic. In this study, the theoretical potential of an alternative treatment combining thermal ablation with low dose rate (LDR) brachytherapy using radioactive magnetic nanoparticles (RMNPs) containing 103-palladium was researched. Methods: The radiation dose characteristics and emission spectra of a single RMNP were calculated, and dose distributions of a commercial brachytherapy seed and an RMNP brachytherapy seed were simulated using Geant4 Monte Carlo toolkit. Results: It was found that the RMNP seeds deliver a therapeutic dose similar to currently used commercial seed, while the dose distribution shows a spherical fall off compared to the more inhomogeneous dose distribution of the commercial seed. Changes in shell thickness only changed the dose profile between 2 × 10−4 mm and 3 × 10−4 mm radial distance to the RMNP, not effecting long-range dose. Conclusion: The dose distribution of the RMNP seed is comparable with current commercial brachytherapy seeds, while anisotropy of the dose distribution is reduced. Because this reduces the dependency of the dose distribution on the orientation of the seed, their surgical placement is easier. This supports the feasibility of the clinical application of the proposed novel treatment modality.

Heterostructured magnetic nanoparticles show great potential for numerous applications in biomedicine due to their ability to express multiple functionalities in a single structure. Magnetic properties are generally determined by the morphological characteristics of nanoparticles, such as the size/shape, and composition of the nanocrystals. These in turn are highly dependent on the
synthetic conditions applied. Additionally, incorporation of a non-magnetic heterometal influences the final magnetic behavior. Therefore, construction of multifunctional hybrid nanoparticles with preserved magnetic properties represents a certain nanotechnological challenge. Here, we focus on palladium/iron oxide nanoparticles designed for combined brachytherapy, the internal form of radiotherapy, and MRI-guided hyperthermia of tumors. The choice of palladium forming the nanoparticle core is envisioned for the eventual radiolabeling with 103Pd to enable the combination of hyperthermia with brachytherapy, the latter being beyond the scope of the present study. At this
stage, we investigated the synthetic mechanisms and their effects on the final magnetic properties of the hybrid nanoparticles. Thermal decomposition was applied for the synthesis of Pd/Fe-oxide nanoparticles via both, one-pot and seed-mediated processes. The latter method was found to provide better control over morphology of the nanoparticles and was therefore examined closely by varying reaction conditions. This resulted in several batches of Pd/Fe-oxide nanoparticles, whose magnetic properties were evaluated, revealing the most relevant synthetic parameters leading to promising performance in hyperthermia and MRI.