Synthesis And Anticancer Study Of Sulfur Dioxide Prodrug

In recent years,an increasing number of new cancer cases has been seen in China,resulting in a heavy medical burden and a declining quality of life.It is urgent to develop new and effective anti-cancer therapies.Cancer cells are more susceptible to oxidative stress than normal cells due to high levels of reactive oxygen species（ROS）caused by REDOX imbalance.Traditional methods of enhancing oxidative stress to treat tumors,such as radiotherapy,photodynamic and chemokinetic therapies,have certain limitations.Gas therapy is a new anticancer treatment,gases such as CO,NO and H₂S have shown potential in fighting various diseases,including cancer.However,little attention has been paid to the anticancer effects of sulfur dioxide（SO₂）.It has been reported that it can effectively deplete the content of reduced glutathione（GSH）in cells,resulting in an increase in ROS levels,and thus can also be used as an anticancer therapy.In this paper,we summarized various reported SO₂ donors and prodrugs,designed and successfully prepared two new SO₂prodrugs on the basis of the previous studies,and made the following progress:1.By bonding 2,4-dinitrophenyl sulfonyl chloride（DNs）to amino acids,a SO₂-containing N-carboxyanhydride（SO₂-NCA）was synthesized by triphosgene method.The polyamino acid SO₂ prodrug was obtained by ring-opening polymerization initiated by polyethylene glycol with terminal amino group.The amphiphilic material can self-assemble into nanoparticles（NPs）in water and be used to carry the anticancer drugβ-lapachone（Lapa）.The results of in vitro experiments showed that after being endocytosed by 4T1 cancer cells,the drug-loaded NPs released SO₂ and Lapa under the action of high concentration of intracellular GSH.SO₂ decreased the concentration of GSH and increased the level of ROS synergistically with Lapa,which eventually led to the apoptosis of cancer cells.At the same time,due to the low content of GSH in normal cells,it is difficult to crack NPs and release Lapa,so it is less toxic to normal cells.Fluorescence imaging detection experiments after in vivo administration in mice showed that the drug-loaded NPs were enriched at the tumor site,probably due to the enhanced permeability and retention effect（EPR）of solid tumors,and the polyamino acid SO₂ prodrug as a nanocarrier achieved tumor targeting.Finally,the in vivo tumor inhibition of the NPs was significantly stronger than that of the free Lapa or blank NPs in 4T1 tumor-bearing mice.2.A SO₂ donor small molecule was grafted onto dodecylamine to obtain a SO₂ small molecule prodrug,and conduct related anti-cancer studies.In addition to the release of SO₂,this material also has a certain degree of biofilm penetration due to the structure of dodecylamine,which can cause cell damage and inhibit tumor growth.DNs was bonded to dodecylamine to obtain a novel SO₂ small molecule prodrug.In addition to releasing SO₂,the prodrug also has a certain biofilm penetration effect due to the structure of dodecylamine,which may cause cell damage and synergistically inhibit the growth of cancer cells.We prepared nanoparticles of this small molecule by nanoprecipitation and characterized their size,morphology,GSH-responsive SO₂ release in detail.The inhibitory or toxic effects of the prodrug nanoparticles on 4T1 cancer cells were investigated by MTT assay.In summary,this article explored the application of SO₂ gas therapy in anti-tumor research on the basis of previous studies,prepared and used new SO₂ prodrug in combination with anticancer drug for anti-tumor treatment.Besides,we developed a new SO₂ small molecule prodrug,and verified its anticancer potential,which provided a new idea for SO₂ gas therapy strategy.