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