Hybrid nanomaterials for metastasis modulation

Metastasis is one of the hallmarks of cancer, and it is considered the final stage of cancer progression. It leads to the development of secondary neoplasms through cancer cells dissemination causing most of the cancer-related deaths and relapses after treatment. Typically, metastasis arises because of the epithelial-to-mesenchymal transition (EMT), which allows cancer cells to lose epithelial features while acquiring mesenchymal properties, such as migration abilities. Regrettably, there are still no specific treatments for cancer at the metastatic stage due to the challenging target. Moreover, the approval process requires antimetastatic drugs to reduce the tumour size, which is not their main outcome by definition, hence discouraging their development.Metal nanomaterials hold the promise to address the metastatic stage through the targeting of molecular pathways or features typical of metastasis. In particular, gold and copper nanoparticles have peculiar features that make them of special interest as antimetastatic agents. Nevertheless, the knowledge about the ADMET of these nanomaterials is limited, preventing the translation to the clinical practice.This thesis demonstrates the intrinsic antimetastatic behaviour of rationally designed metal nano-architectures (NAs) loaded with ultrasmall gold (AuNAs) or copper (CuNAs) nanoparticles or copper complexes (CuLNAs) on pancreatic ductal adenocarcinoma and on glioma models. The investigations have been performed on biomodels of increasing complexity (from 2D cancer cell cultures to chorioallantoic membrane [CAM] models) to account for tumour microenvironment and vascularization. Beside the oncological applications, the wound healing activity of CuNAs has been investigated along with the toxicological profile after a topical administration on burnt skin, and the biokinetics of NAs evaluated upon intranasal instillation, highlighting that an effective metal excretion is critically associated to the nanomaterial design and metal properties.Overall, this thesis work may support the development of novel strategies for the treatment of cancer at the metastatic stage and introduces the very first non-oncological applications of NAs.