Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy  

作　　者：Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin Zhong Zhonggui He Chutong Tian Jin Sun 

机构地区：[1]Department of Pharmaceutics,Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China [2]Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province,Hangzhou 310058,China [3]Joint International Research Laboratory of Intelligent Drug Delivery Systems,Ministry of Education,Shenyang 110016,China [4]Liaoning Provincial Institute of Drug Inspection and Testing,Shenyang 110036,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2024年第2期188-203,共16页亚洲药物制剂科学（英文）

基　　金：supported by National Natural Science Foundation of China(No.82173766,82104109);Natural Science Foundation of Liaoning Province(2022-BS158);Liaoning Province Applied Basic Research Program(No.2022JH2/101300097);National Key R&D Program of China(No.2022YFE0111600).

摘　　要：The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关 键 词：Steric disulfide bond Triglyceride-like pr odrugs CABAZITAXEL Lymphatic transport Oral chemotherapy 

分 类 号：R943[医药卫生—药剂学]