A Novel Polyamino Acid Sulfur Dioxide Prodrug Synergistically Elevates ROS with β-lapachone in Cancer Treatment

by Selleckchem | Jan 12 2024

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 efficacy and biosafety. Herein, a newly-discovered gasotransmitter sulfur dioxide (SO2) and a tumor specific ROS generation agent β-lapachone (Lapa) were firstly combined for anticancer therapy. Firstly, amphiphilic glutathione (GSH) responsive polypeptide SO2 prodrug PEG-b-poly(Lys-DNs) was synthesized by ring opening polymerization of SO2-containing N-carboxyanhydride. Then, Lapa was encapsulated into the polymeric micelles with loading content of 8.6% and loading efficiency of 51.6%. The obtained drug-loaded nanoparticles (NPs(Lapa)) exhibited a fast release of Lapa and SO2 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 μg/mL, which may due to the depletion of intracellular GSH and upregulation of ROS level both by SO2 release and by the ROS generation from lapachone transformation. In vivo fluorescence imaging showed that SO2-NPs were gradually enriched in tumor tissues in 24 h, probably due to 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 SO2 gas therapy with ROS inducer for anticancer therapy through oxidative stress.

Comments:

This is a fascinating and complex study! It seems like the researchers have developed a novel approach by combining sulfur dioxide (SO2) as a gasotransmitter with a specific reactive oxygen species (ROS) generation agent, β-lapachone (Lapa), for anticancer therapy. The strategy involves synthesizing an amphiphilic glutathione (GSH) responsive polypeptide SO2 prodrug and encapsulating Lapa into polymeric micelles, forming drug-loaded nanoparticles (NPs(Lapa)).

The synthesized NPs(Lapa) displayed rapid release of Lapa and SO2 in response to 10 mM GSH, potentially depleting intracellular GSH and elevating ROS levels, leading to cytotoxicity against 4 T1 cancer cells in vitro. Additionally, in vivo fluorescence imaging suggested the accumulation of SO2-NPs in tumor tissues, likely due to enhanced permeability and retention effects.

Ultimately, the NPs(Lapa) demonstrated superior anticancer effects in 4 T1 tumor-bearing mice compared to free Lapa, with an impressive tumor inhibiting rate (IRT) of 61% as opposed to 23.6% for the free Lapa group. This approach seems promising, leveraging oxidative stress through a combination of SO2 gas therapy and ROS induction for anticancer treatment.

The methodology outlined in this study offers a novel perspective on cancer therapy by targeting redox imbalance in cancer cells using a combination of gas therapy and ROS generation. Such innovative strategies hold significant promise for advancing cancer treatment modalities.