Dual-targeting poly(2-oxazoline)-coated porous silicon nanoparticles for improving osteosarcoma therapy

Osteosarcoma is the most prevalent malignant bone tumor in children and adolescents. Current treatment of this aggressive tumor with surgery and chemotherapy is hindered by the non-selectivity of chemotherapeutics, leading to severe toxicity and poor outcomes. This urgent clinical challenge necessitates the need for targeted nanomedicine approaches. We developed dual-targeted poly(2-oxazoline) (POx)-functionalized porous silicon nanoparticles (pSiNPs) loaded with doxorubicin for osteosarcoma therapy. These bespoke nanoparticles with hydrophobic pores displayed high drug loading efficiency (up to 48.7 ± 2.0% w/w) and pH-responsive drug release. Surface decoration with alendronate (ALN) and/or insulin growth factor-2 receptor antibody (Ab) enhanced bone cancer cell targetability. POx is a promising alternative to poly(ethylene glycol) (PEG), and POx-coated pSiNPs revealed comparable anti-fouling properties to PEG. Dual-targeted ALN + Ab-POx@pSiNPs demonstrated three-fold higher cellular association in osteosarcoma cells compared to non-targeted control. They also exhibited enhanced binding affinity to hydroxyapatite crystals in mineralized Saos-2 cells. Importantly, DOX-loaded dual-targeted pSiNPs produced significantly greater cytotoxicity than free DOX, non-targeted, or single-targeted formulations. These findings establish this dual-targeted drug delivery system as potent nanocarrier system for osteosarcoma, combining high payload capacity, controlled release, and selective cancer cell targeting to advance therapeutic outcomes.