Design of Mesoporous Silica Nanoparticles for Crossing the Blood-Brain-Barrier by Modulating Surface Properties

Mesoporous silica nanoparticles (MSNs) have been demonstrated as an excellent platform for drug delivery carriers in cancer treatment where tumor targeting is normally achieved via the enhanced permeability and retention (EPR) effect. However, it remains challenging for MSNs to deliver chemical drugs, nuclear acids, or proteins to reach brain tumors due to the presence of the blood−brain barrier (BBB). Here, we propose a simple strategy to modify MSNs to target brain tumors. Our strategy was to optimize the size of PEG on the surfaces of MSNs to overcome BBB. We first tested different sizes of PEG coating on the MSNS in the in vitro BBB model, where the smaller size of MSNs with near neutral charged (RMSN₂₅-PEG-TA) possesses higher transport efficiency to cross the BBB-mimicking endothelial cell layer. To evaluate the circulation of MSNs, we utilized two-photon microscopy. We observed that the MSNs stayed long enough in the circulation system (over 24 h) and could be accumulated outside of the cerebrovascular in mouse brains. We also examined the EPR effect with various functionalized MSNs. A particular modification in MSNs led to their abundant accumulation in tumor tissue. In a drug delivery study, we explored the potential of using MSNs to deliver drugs (DOX@MSN) into the glioma tumor. It has been observed that the functionalized MSNs with DOX significantly suppress the growth of orthotopic glioma tumors and improved DOX’s severe side effects in vivo study. The biosafety result showed that the given dose of the functionalized MSNs appeared safe and decreased severe side effects caused by DOX in the animal models.