Thiol-Responsive Polypeptide Sulfur Dioxide Prodrug Nanoparticles for Effective Tumor Inhibition

Sulfur dioxide (SO₂) based gas therapy has emerged as a novel anticancer therapeutic strategy because of its high therapeutic efficacy and biosafety. To precisely adjust the SO₂ content and control gas release, herein, a thiol-responsive polypeptide SO₂ prodrug mPEG-block-poly(2-amino-6-(2,4-dinitrophenylsulfonamido)hexanoic acid) (PEG-b-PLys-DNs) was designed and facilely synthesized by polymerization of a novel N-carboxyanhydride SO₂-NCA. The anticancer potential of the self-assembled nanoparticles (SO₂-NPs) was investigated in detail. First, PEG-b-PLys-DNs were synthesized by ring-opening polymerization of SO₂-NCA, which self-assembled into NPs sized 88.4 nm in aqueous. Subsequently, SO₂-NPs were endocytosed into 4T1 cells and quickly released SO₂ under a high concentration of glutathione in tumor cells. This process depleted cellular glutathione, generated reactive oxygen species, and dramatically increased oxidative stress, which led to cancer cell apoptosis. Finally, the in vivo anticancer efficacy of SO₂-NPs was verified in 4T1-tumor-bearing mice. Our results indicated that this novel SO₂ polymeric prodrug has great potential in eradicating tumors.