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

Abstract

Sulfur dioxide (SO 2 ) based gas therapy has emerged as a novel anticancer therapeutic strategy because of its high therapeutic efficacy and biosafety. To precisely adjust the SO 2 content and control gas release, herein, a thiol-responsive polypeptide SO 2 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 SO 2 -NCA. The anticancer potential of the self-assembled nanoparticles (SO 2 -NPs) was investigated in detail. First, PEG-b-PLys-DNs were synthesized by ring-opening polymerization of SO 2 -NCA, which self-assembled into NPs sized 88.4 nm in aqueous. Subsequently, SO 2 -NPs were endocytosed into 4T1 cells and quickly released SO 2 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 SO 2 -NPs was verified in 4T1-tumor-bearing mice. Our results indicated that this novel SO 2 polymeric prodrug has great potential in eradicating tumors.

Sulfur signaling pathway in cardiovascular disease

“…Currently, there is ongoing development of various H 2 S and SO 2 donors or targeted prodrugs. In recent years, different types of SO 2 donors and prodrugs with distinct triggering mechanisms have been designed, including thiol-activated SO 2 prodrugs (Zhang et al, 2023), thermally-activated SO 2 prodrugs (Li et al, 2019), hydrolysis-based SO 2 prodrugs (Day et al, 2016), glutathioneresponsive SO 2 prodrugs (Xia et al, 2022), and esterase-sensitive SO 2 prodrugs (Wang and Wang, 2017). Additionally, H 2 S donors such as CySSPe (Tocmo and Parkin, 2019) and Diallyl trisulfide (Qiao et al, 2018), and the mitochondrial targeting of H 2 S prodrugs AP39 and RT01 (Magierowska et al, 2022), as well as photothermal therapy-triggered H 2 S prodrugs (Chen et al, 2015), have emerged as novel strategies for the treatment of cardiovascular diseases.…”

Sulfur Dioxide (SO2) Releasing Polymeric Systems: Design, Synthesis, and Potential Biomedical Applications

“…(B) Schematic representation of PEG- b -PLys-DNs, aqueous self-assembly, SO 2 release, and mechanism of tumor inhibition. Reproduced from ref. Copyright 2023 American Chemical Society.…”

“…In 2023, Zhang and coworkers designed a thiol responsive SO 2 releasing polypeptide SO 2 prodrug mPEG- block -poly(2-amino-6-(2,4-dinitrophenylsulfonamido)hexanoic acid) (PEG- b -PLys-DNs) for 4T1 tumor inhibition (Figure B) . They developed the polymer PEG- b -PLys-DNs through the ring-opening polymerization of a SO 2 releasing monomer N -carboxyanhydride, SO 2 –NCA.…”

A Novel Cu(II) Loaded Polypeptide SO2 Prodrug Nanoformulation Combining Chemodynamic and Gas Anticancer Therapies

“…This effect can be attributed to the thiol-responsive mechanism described in our previous study. [8,30] As the released SO 2 gas is converted rapidly into bisulfite in aqueous solution, the release profile of SO 2 from the NPs-Cu micelles was investigated by detecting the content of bisulfite using DEACA as the fluorescence probe in a reducing environment. DEACA presents no fluorescence, but fluorescent products can be formed in the presence of bisulfite.…”

“…[26] Our group has focused on polypeptide biomaterials and has developed several biocompatible polymeric nanoparticles (NPs) for anticancer treatment. [27][28][29][30] Herein, we report a novel graft-type polypeptide SO 2 prodrug with GSH-depletion ability and encapsulated Cu(II) for CDT with amplified ROSgenerating ability for cancer therapy (Scheme 1). Firstly, an SO 2 donor with a terminal amine group, N-(2-aminoethyl)−2,4dinitrobenzenesulfonamide (DNs-EDA), was designed and conjugated to PLG-g-mPEG through an amide bond.…”