A Toolbox for the Synthesis of Multifunctionalized Mesoporous Silica Nanoparticles for Biomedical Applications

Mesoporous silica nanoparticles (MSNs) are considered as promising next-generation nanocarriers for healthrelated applications. However, their effectiveness mostly relies on their efficient and surface-specific functionalization. In this contribution, we explored different strategies for the rational multistep synthesis of functional MCM-48-type MSNs with selectively created active inner and/or external surfaces. Functional groups were first installed using a combination of (delayed) co-condensation and post-grafting procedures. Both amine [(3-aminopropyl) triethoxysilane (APTS)] and thiol [(3mercaptopropyl) trimethoxysilane (MPTS)] silanes were used, in various addition sequences. Following this, the different platforms were further functionalized with polyethylene glycol and/or with a pro-chelate ligand used as a magnetic resonance imaging contrast agent (diethylenetriaminepentaacetic acid chelates) and/or loaded with quercetin and/or grafted with an organic dye (rhodamine). The efficiency of the multiple grafting strategies and the effects on the MSN carrier properties are presented. Finally, the colloidal stability of the different systems was evaluated in physiological media, and preliminary tests were performed to verify their drug release capability. The use of MPTS appeared beneficial when compared to APTS in delayed cocondensation procedures to preserve both selective distribution of the functional groups, reactive functionality, and pore ordering. Our results provide in-depth insights into the efficient design of (multi) functional MSNs and especially on the crucial role played by the sequence of step-by-step functionalization methods aiming to produce multipurpose and stable bioplatforms.