Hypoxia-responsive, organic-inorganic hybrid mesoporous silica nanoparticles for triggered drug release

Abstract

Hypoxia is a manifestation of various diseases with an ischemic component, including cancer. Tumor hypoxia is a hallmark of cancer, creating an opportunity to exploit hypoxia to ensure delivery of anticancer drugs to cancer cells. Here, we describe the development of nanoparticles that specifically release drugs under hypoxic conditions. To this end, we prepared a hybrid mesoporous silica nanoparticle, modified to contain 4-(phenylazo)benzoic acid (4-PA, SNA) and β-cyclodextrin (β-CD, SNAC) on the external surface. 4-PA and β-CD act through host-guest interactions to serve as gatekeepers to block the pores of mesoporous sililica nanoparticles (SN), and subsequent selective cleavage of the azo group of 4-PA by intracellular nitroreductases under hypoxic conditions allows the release of entrapped drugs. Under normoxic conditions, doxorubicin (DOX)-loaded SNAC (DOX@SNAC) showed low cytotoxicity, reflecting inhibition of premature release of DOX from SNAC by 4-PA and β-CD. In contrast, under hypoxic conditions, DOX@SNAC showed significant cytotoxicity, similar to that of free DOX. Collectively, these results show that SNAC can function as effective drug-delivery systems in hypoxic conditions. Moreover, these SNACs, hypoxia-responsive hybrid mesoporous silica nanoparticles, could be effective not only in cancer, but also other diseases characterized by ischemic conditions.