Mesoporous Silica Nanoparticles as a Versatile Drug Delivery Carrier for Biologicals and Small Molecules: A study in Pharmaceutical Sciences

Hydrogel-based scaffolds are pivotal in biomedical applications such as tissue engineering and wound extracellular matrix (ECM). This similarity makes them excellent candidates for supporting tissue formation and delivering bioactive cues. Furthermore, hydrogels are highly adaptable materials, capable of being precisely shaped using
semi-solid extrusion 3D printing. Despite these advantages, hydrogels often require reinforcement to enhance their mechanical properties and functionality. A common strategy involves incorporating nanoparticles to form nanocomposite hydrogels, combining the benefits of both hydrogels and nanoparticles. Among the various nanoparticles, mesoporous silica nanoparticles (MSNs) offer exceptional potential in drug delivery due to their tunable particle and pore sizes, large surface
area, and modifiable surface chemistry. These attributes facilitate the adsorption and immobilization of a broad range of therapeutic active agents, including small
molecules and biomacromolecules. This thesis aims to fabricate MSN-reinforced naturally derived hydrogels suitable for delivery and immobilization of hydrophobic small-molecule drugs as well as biological proteins. Additionally, it investigates the interactions at three key interfaces within MSN-based nanocomposites and their influence on the
therapeutic outcomes: (1) between MSNs and loaded cargo, (2) between MSNs and the hydrogel matrix, and (3) between MSNs and cells cultured within the
matrix. Thus, MSNs with varying pore sizes were synthesized to match the molecular sizes of the molecular cargo to be loaded (drugs and proteins). Surface
functionalization with neutral, positively and negatively charged functional groups were employed to optimize loading capacity and assess the influence of net surface charge on protein activity, matrix compatibility, and intracellular delivery. The adsorption of three distinct model proteins (bovine serum albumin, horseradish peroxidase, lysozyme) onto surface-modified MSNs was optimized. Due to their structural sensitivity, the biological activity of immobilized proteins was evaluated for potential applications in nanocomposite hydrogels. MSNs with suitable surface modifications that provide optimal loading capacity and preserve
biological activity, were used for fabricating nanocomposite hydrogels. The compatibility, rheological properties, and homogeneity of MSN-incorporated
naturally derived hydrogels were thoroughly assessed. Different surface modifications of MSNs significantly influenced their compatibility and
homogeneity within the matrix. Protein-loaded MSNs were further evaluated for 3D printability, protein release, and retention of biological activity after release
from the 3D scaffolds, with a particular focus on the effect of crosslinking method on the biological activity. For intracellular delivery, hydrophobic drug-loaded
MSNs with different surface charges were integrated into cell-laden hydrogel scaffolds. Drug delivery efficacy was evaluated in two biomedical contexts: tissue engineering and in vitro tumor modeling. Surface modified MSNs demonstrated an enhanced biological response compared to plain MSNs.
This thesis provides a basis for a deeper understanding of nano-biointerfaces and their impact on the therapeutic performance of MSN-reinforced hydrogel systems,
offering valuable insights into the design of advanced drug delivery platforms.