Molecular Polymer Bottlebrushes with Tunable Hydrophilic-Hydrophobic Character and their Interaction with Serum Proteins, Cancer Cells and Tumours

Abstract

The development of nanoparticles as drug delivery systems has greatly improved prospects of more selective and safer drug delivery to tumours, by conferring enhanced pharmacokinetic properties compared to free anti-cancer drugs. The improvements afforded by these nanosized systems remains marginal at this point, due to physiological barriers raised by the unique tumour microenvironment as well as the protein corona which forms around nanoparticles upon their introduction into biological environments. Hence, the chosen nanocarrier must have its physicochemical parameters carefully adjusted to surmount these barriers and achieve sufficient tumour accumulation levels. In that regard, the hydrophilic-hydrophobic balance of nanoparticles has remained mostly unexplored as a determinant of their behaviour in vivo. In the first research chapter, we investigated this knowledge gap using a library of molecular polymer bottlebrushes (MPBs) with varied hydrophobicity levels to explore how hydrophobicity impacts their tumour penetration efficiency. Although this parameter had a marginal influence in vitro, its’ effects were more pronounced in tumour-bearing mice, where favourable biodistribution, initial tumour uptake and retention was favoured by moderately hydrophobic MPBs In the second research chapter, we extended our investigation to probe how the hydrophilic-hydrophobic balance of nanoparticles governed the adsorption of serum proteins and their interactions with cellular membranes. Although the results demonstrated that the MPBs affinity for serum albumin was unaffected by their hydrophobicity, the presence of serum proteins had a significant outcome on the MPBs’ uptake into cancer cells and biomimetic cell membranes. In particular, a correlation between MPB hydrophobicity and membrane disruption and cancer cell association was apparent solely when the particles were co-incubated with serum proteins.