NO prodrug-conjugated, self-assembled, pH-responsive and galactose receptor targeted nanoparticles for co-delivery of nitric oxide and doxorubicin

Abstract

Targeted delivery and controlled release of nitric oxide (NO) locoregionally are in high demand and challenging in cancer treatment. Herein, we report an example of galactose receptor targeted, pH-responsive and self-assembled nanoparticle-based delivery of the NO prodrug O²-(2,4-dinitrophenyl) 1-[4-(propargyloxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (alkynyl-JSK), which was chemically conjugated to an amphiphilic block copolymer through a click reaction for the first time. The assembled NO prodrug nanoparticles show high NO capacity (the content of the NO prodrug in the copolymer, ∼23.4% (w/w)), good stability and a sustained NO release pattern with unique glutathione/glutathione S-transferase (GSH/GST) activated NO-releasing kinetics. Such NO-loaded nanoparticles exhibit superior cytotoxicity to HepG2 cells. More importantly, in combination with doxorubicin (DOX) chemotherapy a significant synergistic therapeutic effect was achieved, due to its excellent galactose receptor-targeting capability, rapid acid-triggered DOX release and sustained NO release. Our findings indicate that these multifunctional nanoparticles can serve as an efficient NO and chemotherapeutic agent delivery platform, holding great promise in cancer combinatorial treatment.