Design and evaluation of nanoparticle-based delivery systems: towards cancer theranostics

The design, characterization and applicability of nanoparticle (NP)-based delivery systems intended for cancer theranostics, are presented in this thesis. Mesoporous silica nanoparticles (MSNs) have been widely established as biocompatible and efficient carriers of hydrophobic molecules, such as drugs for in vitro and in vivo tumor targeting. Although their intracellular delivery and cargo release have been demonstrated, knowledge of the underlying drug release mechanisms still remain unclear. For future control and prediction of these parameters, which from a clinical perspective are imperative to all drug delivery systems (DDSs), the release of hydrophobic cargo from MSNs is studied. In simple aqueous solvents, cargo release is strongly associated with nanocarrier degradation, whereas in media mimicking intracellular conditions, where lipids or hydrophobic structures are present, the physicochemical properties of the cargo molecule itself and its interactions with the surrounding medium are the release-governing parameters. For comparison, the relationship between intracellular cargo release and degradation of poly(alkylcyanoacrylate) (PACA) nanocarriers is also investigated, for which the release is found to be dependent on the biodegradation of the carrier. The influence of NP monomer composition on intracellular delivery and the role of different endocytosis pathways are also assessed.This thesis moreover presents a novel multifunctional composite NP for combined optical imaging, tracking and drug delivery. The used approaches include creation and optimization of core-shell nanostructures of photoluminescent (PL) nanodiamonds (NDs) encapsulated within mesoporous silica shells that allow tuning of the composite NP size and loading of hydrophobic cargo molecules. Through subsequent surface engineering, efficient passive uptake by endocytosis, followed by intracellular release of cargo, is achieved and displayed by optical fluorescence imaging. The approaches presented in this thesis are highly interdisciplinary, placed at the meeting point between chemistry, physics, engineering, biotechnology and pharmaceutical sciences, and provide a basis for the rational design and evaluation of NP-based DDSs, intended for cancer theranostics, mainly by intravenous (IV) administration.