Testing nanoparticles for brain drug delivery

Remarkable progress has been achieved in the last years in the use of nanometric systems in biomedicine. In particular, the use of nanoparticles (NPs) for diagnostic and therapeutic approaches to brain diseases has raised considerable attention. Nanotechnological approaches exploiting NPs as carriers for targeted brain delivery across the blood-brain barrier could thus provide alternatives to conventional therapies. In addition, NPs could be of use for the intracerebral delivery of drugs, an approach which, though invasive, could be applicable to severe neurological diseases, especially in view of the recent, increasing use of stereotaxic neurosurgery. Stemming from the search to transport across the blood-brain barrier a drug used to cure a severe parasitic brain infection, the present experimental project focused on i) the in vitro evaluation of viability effects of different NPs in a motor neuron cell line, as model of neuronal interaction and in human dendritic cells, involved in the immune responses, ii) testing the penetration in the brain parenchyma of the same NPs after systemic injection; iii) assessing, at the molecular and cellular levels the inflammatory response of the brain parenchyma to the intracerebral administration of a variety of NPs, and its neurotoxic effects. In the first part of the doctoral project, in vitro and in vivo studies were performed with metal-based NPs and polymer-based NPs. Metallic NPs showed a mild in vitro reaction after short time, while at longer time intervals, NPs accumulated in the cells, probably due to cell functions and viability that were not altered. Polymeric NPs were functionalized to verify whether this could increase brain targeting. In vitro studies assessed that these NPs did not cause cytotoxicity or immune response activation, indicating their potential use as drug delivery carriers. The in vivo experimental study, performed in adult mice, was aimed at verifying whether these NPs can reach the brain parenchyma from the blood stream and the response of glial cells. The results indicated that metal-based NPs accumulated mainly in peripheral organs (liver and spleen) after iv injection, but they were also detected, though in very limited amounts, in the brain parenchyma. A mild activation of glial cells was detected by immunophenotyping. In the second part of the doctoral project, well-known soft liposomes and novel hard carbon-based nanomaterials were injected directly in mouse brain. This paradigm was used to determine whether the nanomaterials induced, at different time intervals, gene expression changes which are part of the brain inflammatory response, and, at the cellular level, neuronal cell death and glial cell activation. Carbon-based nanomaterials elicited a weak and local inflammatory response in comparison with liposomes. Based on these observations, functionalized polymer-based NPs and carbon nanomaterials could represent candidate nanotools for intracerebral drug delivery systems. Due to their properties of biodegradability and biocompatibility, together with the possibility to increase brain targeting with specific ligands, functionalized polymeric NPs could be better suited for brain targeting by peripheral administration.