Theranostic silica nanoparticles for selective and simultaneous delivery of paclitaxel and coumarin to hypoxic tumors.

Theranostic nanomaterials, that combine diagnostic imaging with drug delivery, have emerged as a promising alternative to conventional oncology therapy. Tumor hypoxia and the poor solubility of chemotherapeutics like paclitaxel (PTX) remain critical obstacles in oncology. To address these challenges, we have developed hypoxia-responsive theranostic mesoporous silica nanoparticles for the selective delivery of PTX and a coumarin fluorescent dye to hypoxic tumors. The silica nanocarrier is capped with a molecular gate containing a masked coumarin fluorophore attached to a nitro-containing self-immolative spacer. Upon exposure to nitroreductases (NTR), enzymes overexpressed in hypoxic tumor microenvironments, the gate undergoes a self-immolation reaction, triggering the simultaneous release of the cargo and the activation of coumarin fluorescence. This design allows for real-time monitoring of drug release. In vitro assays demonstrated that the nanocarriers selectively reduced the viability of A549 lung cancer cells under hypoxic conditions while exhibiting high biocompatibility with healthy THP-1 macrophages in normoxia. Moreover, in vivo studies using a zebrafish xenograft model confirmed effective tumor accumulation and significant tumor regression (34% reduction) compared to controls, with reduced systemic toxicity. This proof-of-concept establishes the potential of these NTR-responsive theranostic MSNs as versatile multifunctional nanocarriers integrating diagnostic tracking with targeted therapeutic release in hypoxic environments.