Evaluation of the Role of Glycans of the Biomolecular Corona and Development of Well-Characterised Glyco-Nanoparticles for Biomedical Applications

Abstract

Nanoparticles (NPs) have gained great attention in medicine thanks to their advantageous properties that make them excellent candidates for application in modern medicine. In particular, the NP surface can be tailored and modified with targeting moieties to increase the localisation in diseased areas. Despite these advantages, several drawbacks are decreasing the implementation of clinical trials and there is a need to tackle several issues.Upon intravenous injection, NPs encounter biological barriers resulting in macrophage uptake and liver accumulation and low circulation half-time. Additionally, their surface is dramatically altered by the adsorption of biomolecules with high affinity towards the NP surface, which can dramatically affect the NPs’ biodistribution and accumulation, thus their therapeutic efficacy. In the last decades, several studies have been focused on the correlation between the NP physico-chemical properties, corona formation and biological outcome, and it has become a regulatory burden as this phenomenon is too complex to be studied and it has too many variables. As the protein corona is formed by glycosylated plasma proteins, it is possible to speculate that these glycans become part of the corona. Additionally, glycans modulate several biological processes, including protein clearance and inflammation. Several studies have focused on the development of NPs with longer circulation half-time. A typical approach is the surface functionalisation with stealth polymers, such as PEG. However, increasing studies have shown that PEG can lead to complement activation, pseudo-allergies and to the development of anti-PEG antibodies. Therefore, there is the need to develop biocompatible polymers.In this thesis, I have carried out a deep corona characterisation using citrate gold NPs, where I have identified the glycan types on the corona proteins and I have shown with different techniques that these glycans are biologically accessible and capable of interacting with specific receptors. I have also evaluated whether glycans can be used as biomolecules to increase the NP circulation half-life by attenuating the protein corona formation, and increase the nanomaterial biocompatibility by masking PEG and modulate the immunological response. I have developed a novel platform for characterisation.</p