Hyaluronic Acid-Modified Polymeric Gatekeepers on Biodegradable Mesoporous Silica Nanoparticles for Targeted Cancer Therapy

Systemic administration of mesoporous silica nanoparticles (MSNs) in biomedical applications has recently been questioned because of poor degradability, which is necessary for the successful development of new drug-delivery systems. Herein, we report the development of colloidal-state-degradable MSNs functionalized with versatile polymer-gatekeepers with a cancer-cell-targeted moiety. The polymer MSNs (PMSNs) were designed with disulfide cross-linking enabling safe encapsulation until cargos are delivered to target cancer cells. Selective targeting was achieved by decoration of CD44-receptor-targeting ligands, hyaluronic acid (HA), with HA-PMSNs. The selective cellular uptake mechanism of the fabricated targeted nanocarrier into CD44-overexpressed cancer cells was demonstrated through the clathrin- and macropinocytosis-mediated pathways. Upon internalization into cancer cells, doxorubicin loaded into the HA-PMSNs can be released by degradation of the polymer shells in the reducing intracellular microenvironment that consequentially induces cell death and further degradation of the MSNs. This study offers a simple technique to fabricate a versatile drug carrier with a high drug loading capacity.