Polyelectrolyte Complex Templated Synthesis of Silica Nanoparticles with Intrinsic Functionality for Biomedical Application

Coacervation, the liquid-liquid phase separation of a solution of charged macromolecules into macromolecule rich and depleted phases, can give both nano- and macro- scale polyelectrolyte complexes (PECs) that are desirable for biomedical application. The ease of formation under mild conditions makes the PECs ideal candidates for the encapsulation of therapeutic molecules, while the range of macromolecules which may be incorporated allows the introduction of biomedically beneficial properties for example cancer targeting or stimuli responsive drug release. However, their sensitivity to environmental changes in pH, ionic strength, and temperature can lead to poor stability which can limit their potential application. Silica nanoparticles (SiNPs), on the other hand, demonstrate good stability under these environmental changes, but typically do not exhibit biomedically desirable surface functionalities without extensive multi-stage synthetic protocols. This thesis aims to use PECs as multifunctional scaffolds for SiNP synthesis, hence combining the ease of PEC formation and intrinsic macromolecule functionality to enhance anticancer drug delivery.
This is first demonstrated with the formation of arginine (Arg)/poly(acrylic acid) (PAA) PECs which serve as templates for the synthesis of highly monodispersed sub-100 nm porous SiNPs with intrinsic Arg and PAA surface functionality (Arg/PAA-PSiNPs). The retention of PAA enabled a high doxorubicin hydrochloride (Dox) loading capacity and a 4-fold increase in drug release under weakly acidic pH compared to physiological pH. The surface presentation of Arg conferred significantly higher intracellular accumulation of Arg/PAA- PSiNPs in patient-derived glioblastoma cells compared to non-tumorigenic neural progenitor cells, which effectively translated to lower IC50 values with Dox-loaded Arg/PAA-PSiNPs than non-functionalised PSiNPs. The synthesis pathway was also extended to the synthesis of poly(ethyleneimine) functionalised SiNPs (PEI-SiNPs) formed from soft PEC templates of PEI and glutamic acid. Through their polycationic surface functionality, the PEI-SiNPs acted as multifunctional electrostatic crosslinkers with hyaluronic acid to form nanocomposite coacervate hydrogels with tunable mechanical stiffness. The reversible electrostatic interactions within the hydrogel networks enabled self-healing and thixotropic properties, and the excess positive charge present within the PEI-SiNPs facilitated high loading and retarded the release of the anionic anti-cancer drug methotrexate. These systems show great potential for further evaluation in in vivo animal models, and bring forward new insights for the development of SiNPs with built-in functionalities for biomedical applications.