A Novel Polyamino Acid Sulfur Dioxide Prodrug Synergistically Elevates ROS with b-Lapachone in Cancer Treatment

Due to the distorted redox balance, cancer cells are considered more vulnerable to excessive reactive oxygen species (ROS). In a variety of oxidative stress-related therapies, gas therapy has emerged as a new therapeutic strategy owing to its eff icacy and biosafety. Herein, a newly-discovered gasotransmitter sulfur dioxide (SO 2 ) and a tumor speci fic ROS generation agent b -lapachone (Lapa) were firstly combined for anticancer therapy. Firstly, amphiphilic glutathione (GSH) responsive polypeptide SO 2 prodrug PEG- b -poly(Lys-DNs) was synthesized by ring opening polymerization of SO 2 -containing N -carboxyanhydride. Then, Lapa was encapsulated into the polymeric micelles with loading content of 8.6 % and loading ef ficiency of 51.6 %. The obtained drug-loaded nanoparticles (NPs(Lapa)) exhibited a fast release of Lapa and SO 2 in the stimuli of 10 mM GSH in PBS. Subsequently, in vitro experiment showed that NPs(Lapa) exhibited obvious cytotoxicity towards 4 T1 cancer cells at a concentration of 2.0 m g/mL, which may be attributed to the depletion of intracellular GSH and upregulation of ROS level both by SO 2 release and by the ROS generation from lapachone transformation. In vivo fluorescence imaging showed that the NPs were gradually enriched in tumor tissues in 24 h, probably due to the enhanced permeability and retention effect of NPs. Finally, NPs(Lapa) showed the best anticancer effect in 4 T1 tumor bearing mice with a tumor inhibiting rate (IRT) of 61 %, whereas IRT for free Lapa group was only 23.6 %. This work may be a new attempt to combine SO 2 gas therapy with ROS inducer for anticancer therapy through oxidative stress. (c) 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.