Weiran Ma,1,2 Xiaoying Wang,2 Dongqi Zhang,3 Xupeng Mu1 

1Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of China; 2Jilin University School of Pharmaceutical Sciences, Changchun, 130021, People’s Republic of China; 3Department of Urology, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China

Correspondence: Xupeng Mu, Email muxupeng@jlu.edu.cn

Abstract: Cancer poses a significant threat to human life and health. Chemotherapy is currently one of the effective cancer treatments, but many chemotherapy drugs have cell toxicity, low solubility, poor stability, a narrow therapeutic window, and unfavorable pharmacokinetic properties. To solve the above problems, target drug delivery to tumor cells, and reduce the side effects of drugs, an anti-tumor drug delivery system based on tumor microenvironment has become a focus of research in recent years. The construction of a reduction-sensitive nanomedicine delivery system based on disulfide bonds has attracted much attention. Disulfide bonds have good reductive responsiveness and can effectively target the high glutathione (GSH) levels in the tumor environment, enabling precise drug delivery. To further enhance targeting and accelerate drug release, disulfide bonds are often combined with pH-responsive nanocarriers and highly expressed ligands in tumor cells to construct drug delivery systems. Disulfide bonds can connect drug molecules and polymer molecules in the drug delivery system, as well as between different drug molecules and carrier molecules. This article summarized the drug delivery systems (DDS) that researchers have constructed in recent years based on disulfide bond drug delivery systems targeting the tumor microenvironment, disulfide bond cleavage-triggering conditions, various drug loading strategies, and carrier design. In this review, we also discuss the controlled release mechanisms and effects of these DDS and further discuss the clinical applicability of delivery systems based on disulfide bonds and the challenges faced in clinical translation.

Keywords: disulfide bond, drug delivery systems, tumor microenvironment, GSH/ROS