Caprifico, Anna Eleonora (2022) Alkyl glyceryl chitosan-based nanocarriers for drug delivery to the brain. (PhD thesis), Kingston University, .
Abstract
Treatment of malignant brain tumours is hindered by the blood-brain barrier (BBB), which may be overcome by nanomedicine, a strategy of brain-targeted drug delivery. Chitosan(Cs) is a natural polymer widely employed in this context since it can cross the BBB by adsorptive endocytosis. Moreover, Cs structure is susceptible to chemical functionalization so to improve its physical and chemical properties, which would boost the passage through the BBB. For instance, the functionalisation of Cs using alkylglycerols has shown to increase the hydrophobicity of the novel polymer, hence improving the crossing of the nanocarrier (NC) through the phospholipid bilayer of the cerebral endothelial cells. Therefore, the aim of this work was to synthesise and characterize several types of alkyl glyceryl-modified Cs,to be used in the generation of NCs (nanoparticles (NPs) and as surface coating of carbon (nanotubes). Selected polymers such as the butyl glyceryl Cs were used in the subsequent studies: for instance, the ability to adsorb serum proteins once dissolved in biological fluids and the brain tumour-associated microglial response were assessed. Moreover, C's and butyl glyceryl C's were conjugated to fluorescein isothiocyanate before NPs generation and the cellular uptake of these NP's was assessed by fluorescence means in several cell lines including cancer cells (Caco-2 and HeLa), microglia (SIM-A9) and cerebral endothelial cells (hCMEC/D3), after developing an in vitro model of the BBB. Results showed that the butyl glyceryl Cs was the most promising polymer; this generated highly monodispersed NPs, characterized by high stability in the biological fluids, cellular uptake, and disruption of tight junctions of the BBB. However, further quantitative investigations would determine whether the presence of the butyl chain on Cs structure is effective in boosting the passage of NPs through the cerebral endothelial cell monolayer, for the delivery of therapeutic agents to the brain.
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