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PhD Student: Aritz Lafuente López de Arbina

Directors: Dr Alejandro Gomez, Senior Researcher in the Magnetic Nanostructures at ICN2 and Dr Borja Sepúlveda, at CSIC

Short Abstract:

Cancer is one of the leading causes of death worldwide, and the development of new nanotechnology-based therapies is not meeting the expectations due to the poor accumulation and rapid elimination of nanoparticles. Therefore, the development of new therapeutic modalities that allow for external control and monitoring of the evolution of nanotherapies is necessary.

In this thesis, a simple, scalable, and adaptable method for manufacturing drug-loaded nanoparticles (~150 nm) partially covered with a few nanometers of metal (nanodomes) was developed. Firstly, the versatility of the manufacturing strategy with different metals and their application in different biological systems was demonstrated. For example, copper nanodomes with the antibiotic erythromycin showed a synergistic behaviour, reducing 2.5-fold required amount of antibiotic. In the case of gold nanodomes loaded with the photodynamic agent (indocyanine green), a combinatory effect of photothermal and photodynamic therapy was demonstrated, reducing tumour growth by a factor of 3.5.

On the other hand, opto-magnetic iron nanodomes, designed to have a vortex magnetic configuration, which was crucial for maintaining high colloidal stability, were studied in depth for nanomedical applications. The iron cap provided strong magnetization, allowing strong magnetic manipulation through magnetophoretic forces, resulting in a magnetic concentration that was 2.2-fold higher than the passive injection in mouse tumours. The metal iron cap also provided intense T₂ contrast in nuclear magnetic resonance imaging, allowing non-invasive tracking of the nanodomes. Additionally, the iron semi-cover exhibited a highly damped plasmonic behaviour, maximizing the light absorption and reducing the scattering. This combination resulted in high photothermal efficiency in the near-infrared region, which could be applied to produce local mild hyperthemial to boost the drug effects and kill cancer cells. This approach combining photothermal with magnetic manipulation was demonstrated to be highly effective in xenograft mouse models of breast cancer, requiring drug doses 100-500 times lower than the free drug paclitaxel. A combinatory therapy for chemo-resistant head and neck cancer was also explored, showing promising results.

Alternatively, to enhance even further the therapeutic efficacy, iron nanodomes loaded with docetaxel drug were incorporated into monocytes (THP1@NDs), as cellular vehicle capable of: i) crossing cellular barriers, ii) evading the immune system, and iii) being externally controlled by light and magnetic fields. The therapeutic efficacy was demonstrated in realistic 3D bioprinted cancer model, featuring endothelial barrier, cancer spheroids, stromal cells and extracellular matrix. It was shown that, in the presence of a magnetic gradient, the THP1@NDs showed much deeper penetration into the bioprinted matrix. Exploiting the synergistic photothermal action, a 50% reduction in viability was achieved compared to the control, preferentially inducing apoptosis, whereas the free drug did not generate any therapeutic effect.

Finally, cellular vehicles based on macrophages with pro-inflammatory phenotype differentiated from monocytes was proposed to modulate the immune response in the tumour microenvironment, as a strategy to eliminate it. Preliminary results indicated both activation and repolarization of primary human macrophages by both the nanodomes and nanodomes loaded with the drug imiquimod, an immune response modulator.

In conclusion, this thesis has enabled the development of novel drug-loaded optomagnetic nanodomes for the development of new therapies combining light, magnetic fields, and cellular vehicles, with promising nanomedicine potential.