Straightforward adsorption-based formulation of mesoporous silica nanoparticles for drug delivery applications

Mesoporous silica nanoparticles (MSNs) have emerged as a very promising drug delivery platform. However, multi-step synthesis and surface functionalization protocols rise the hurdle for translation of this promising drug delivery platform to the clinic. Furthermore, surface functionalization aiming at enhancing the blood circulation time, typically through surface functionalization with poly(ethylene glycol) (PEG) (PEGylation), has repeatedly been shown to be detrimental for the drug loading levels that can be achieved. Here, we present results related to sequential adsorptive drug loading and adsorptive PEGylation, where the conditions can be chosen so that the drug desorption during PEGylation is minimized. At the heart of the approach is the high solubility of PEG both in water and in apolar solvents, which makes it possible to use a solvent for PEGylation in which the drug exhibits a low solubility, as demonstrated here for two model drugs, one being water soluble and the other not. Analysis of the influence of PEGylation on the extent of serum protein adsorption underline the promise of the approach, and the results also allow the adsorption mechanisms to be elaborated. Detailed analysis of the adsorption isotherms enables determination of the fractions of PEG residing on the outer particle surfaces in comparison to inside the mesopore systems, and also makes it possible to determine the PEG conformation on the outer particle surfaces. Both parameters are directly reflected in the extent of protein adsorption to the particles. Finally, the PEG coating is shown to be stable on time-scales compatible with intravenous drug administration, which is why we are convinced that the presented approach or modifications thereof will pave the way for faster translation of this drug delivery platform to the clinic.