Chitosan oligosaccharide-functionalized nano-prodrug for cascade chemotherapy through oxidative stress amplification

Lan Cui; Qingqing Xu; Weishuang Lou; Yali Wang; Xuelian Xi; Yanlin Chen; Mengyao Sun; Zihua Wang; Pengshuai Zhang; Shuoye Yang; Lu Zhang; Lingbo Qu

doi:10.1016/j.ijbiomac.2024.131641

Chitosan oligosaccharide-functionalized nano-prodrug for cascade chemotherapy through oxidative stress amplification

Int J Biol Macromol. 2024 Apr 18;268(Pt 2):131641. doi: 10.1016/j.ijbiomac.2024.131641. Online ahead of print.

Authors

Affiliations

¹ College of Biological Engineering, Henan University of Technology, Zhengzhou 450001, PR China; College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: cuilanmm56@163.com.
² College of Biological Engineering, Henan University of Technology, Zhengzhou 450001, PR China.
³ College of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China.

PMID: 38641277
DOI: 10.1016/j.ijbiomac.2024.131641

Abstract

Redox nanoparticles have been extensively developed for chemotherapy. However, the intracellular oxidative stress induced by constant aberrant glutathione (GSH), reactive oxygen species (ROS) and gamma-glutamyl transpeptidase (GGT) homeostasis remains the primary cause of evading tumor apoptosis. Herein, an oxidative stress-amplification strategy was designed using a pH-GSH-H₂O₂-GGT sensitive nano-prodrug for precise synergistic chemotherapy. The disulfide bond- conjugated doxorubicin prodrug (DOX-ss) was constructed as a GSH-scavenger. Then, phenylboronic acid (PBA), DOX-ss and poly (γ-glutamic acid) (γ-PGA) were successively conjugated using chitosan oligosaccharide (COS) to obtain the nano-prodrug PBA-COS-ss-DOX/γ-PGA. The PBA-COS-ss-DOX/γ-PGA prodrug could tightly attach to the polymer chain segment by atom transfer radical polymerization. Simultaneously, the drug interacted relatively weakly with the polymer by encapsulating ionic crosslinkers in DOX@PBA-COS/γ-PGA. The disulfide bond of the DOX-ss prodrug as a GSH-scavenger could be activated using overexpressed GSH to release DOX. Particularly, PBA-COS-ss-DOX/γ-PGA could prevent premature drug leakage and facilitate DOX delivery by GGT-targeting and intracellular H₂O₂-cleavable linker in human hepatocellular carcinoma (HepG2) cells. Concurrently, the nano-prodrug induced strong oxidative stress and tumor cell apoptosis. Collectively, the pH-GSH-H₂O₂-GGT responsive nano-prodrug shows potential for synergistic tumor therapy.

Keywords: Chitosan oligosaccharide; Oxidative stress; Prodrug.