A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma  

作　　者：Lin An Peng Zhang Wei Shen Xuan Yi Weitian Yin Rihua Jiang Chunsheng Xiao 

机构地区：[1]Department of Hand Surgery and Department of Dermatology,China-Japan Union Hospital of Jilin University,Changchun,130033,PR China [2]Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun,130022,PR China [3]Jilin Biomedical Polymers Engineering Laboratory,Changchun,130022,PR China

出　　处：《Bioactive Materials》2021年第5期1365-1374,共10页生物活性材料（英文）

基　　金：supported by the National Natural Science Foundation of China(51803209,51773196,and 51573184);the Jilin Provincial Science and Technology Development Program(20190201205JC,20190103022JH,and 20190103038JH);the Youth Innovation Promotion Association of Chinese Academy and Sciences(2017266).

摘　　要：Melanoma,as the most aggressive and treatment-resistant skin malignancy,is responsible for about 80%of all skin cancer mortalities.Prone to invade into the dermis and form distant metastases significantly reduce the patient survival rate.Therefore,early treatment of the melanoma in situ or timely blocking the deterioration of metastases is critical.In this study,a sulfur dioxide(SO_(2))polymer prodrug was designed as both an intracellular glutathione(GSH)-responsive SO_(2) generator and a carrier of doxorubicin(DOX),and used for the treatment of subcutaneous and metastatic melanoma.Firstly,chemical conjugation of 4-N-(2,4-dinitrobenzenesulfonyl)-imino-1-butyric acid(DIBA)onto the side chains of methoxy poly(ethylene glycol)grafted dextran(mPEG-g-Dex)resulted in the synthesis of the amphiphilic polymer prodrug of SO_(2),mPEG-g-Dex(DIBA).The obtained mPEG-g-Dex(DIBA)could self-assemble into stable micellar nanoparticles and exhibited a glutathione-responsive SO_(2) release behavior.Subsequently,DOX was encapsulated into the core of mPEG-g-Dex(DIBA)micelles to form DOX-loaded nanoparticles(PDDN-DOX).The formed PDDN-DOX could be internalized by B16F10 cells and synchronously release DOX and SO_(2) into the tumor cells.As a result,PDDN-DOX exerted synergistic anti-tumor effects in B16F10 melanoma cells because of the oxidative damage properties of SO_(2) and toxic effects of DOX.Furthermore,in vivo experiments verified that PDDN-DOX had great potential for the treatment of subcutaneous and metastasis melanoma.Collectively,our present work demonstrates that the combination of SO_(2)-based gas therapy and chemotherapeutics offers a new avenue for inhibiting melanoma progression and metastases.

关 键 词：Glutathione-responsive Melanoma Polymer prodrug Sulfur dioxide 

分 类 号：R739.5[医药卫生—肿瘤]