Nanobiomaterials for biological barrier crossing and controlled drug delivery

Nanoscale delivery systems that respond to external stimuli or internal cues in the cellular microenvironment aiming for on demand cargo release, are of great interest for the controlled delivery of therapeutic compounds at disease targets. However, to create these systems a deep understanding of nanomaterial-cell interactions is necessary. In Chapter 2 of this thesis, the internalization of nanogels (NGs) with different stiffnesses by brain endothelial cells and its inverse correlation with their ability to cross the blood-brain barrier (BBB) is described; Harder NGs showed a higher uptake, while softer NGs exhibited an enhanced capacity of crossing the BBB. The same NGs were employed in Chapter 2 to assess the effect of stiffness on the uptake of nanogels in 2D monocultures and a co-culture of glioma cells and macrophages. A preferred internalization of harder NGs was observed, although softer NGs showed a higher cytotoxic effect. In co-culture, the toxic effect was reduced, likely due to changes in macrophage phenotype as induced by factors secreted by glioma cells. Chapter 4 addresses the development and in vitro evaluation of breast cancer cell membrane-coated polymeric nanocarriers (NCs) containing paclitaxel as a model drug. The membrane-coated NCs significantly reduced cell viability of breast cancer cells when compared to non-coated NCs, but did not affect other epithelial cell types. To conclude, Chapter 5 describes the development of a light-inducible drug delivery system employing light-activated molecular motors (MMs). The incorporation of MMs in liposomes yielded a controllable light-responsive release system through reversible destabilization of the lipid bilayer.