EUROPEAN CONGRESS AND EXHIBITION ON ADVANCED MATERIALS AND PROCESSES - EUROMAT 2021

Despite more than a century of research to achieve oral delivery insulin, the current clinical reality remains unchanged in terms of therapeutic administration, due to the challenge of overcoming gastrointestinal barriers. It has been recently reported by our group that with the use of dendritic mesoporous silica nanoparticles (DMSNs) together with a protein-based excipient, succinylated $\beta$-lactoglobulin (BL), pH-responsive tablets could prevent the premature gastric release and degradation of encapsulated insulin. However, there are still open issues related to colloidal stability, control of release rate, permeation enhancement and mucoadhesion, which need to be addressed before reaching in vivo tests. To this aim, we focus our studies on the examination of the influence of surface chemistry/charge and colloidal stability of DMSNs on the loading efficiency and insulin release performances. For this, DMSNs (130 nm; pore size: 7.0 nm) were functionalized with polyethylene glycol (PEG, 2 kDa) and a phosphonate-silane, trihydroxysilylpropyl methylphosphonate (THMP), introduced through different post-grafting strategies. The functionalized DMSNs (DMSNs-PEG and DMSNs-PO$_3$) exhibited an enhanced colloidal stability in aqueous and saline media (PBS) over a wide pH range. Different formulations for oral administration were prepared by mixing BL with pure and functionalized DMSNs containing insulin (20 % w/w) and preliminary release tests were performed with simulated body fluids. Compared to a DMSNs-free formulation, encapsulated insulin was even more protected and the release was lowered down to acceptable threshold (less than 10 %) at pH 1.2, while at pH 7.4 controlled release could be reached for 24 h. The analysis of the released insulin confirmed that drug confinement into the pores of the hybrid DMSNs did not affect the peptide structure. The ability of DMSNs to be internalized by intestinal cells was tested using healthy human epithelial colon cells (HCEC) through live cell imaging, observing enhanced cell uptake of insulin.