Trisulfide bond-mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity.

Abstract

Rational design of nanoparticulate drug delivery systems (nano-DDS) for efficient cancer therapy is still a challenge, restricted by poor drug loading, poor stability, and poor tumor selectivity. Here, we report that simple insertion of a trisulfide bond can turn doxorubicin homodimeric prodrugs into self-assembled nanoparticles with three benefits: high drug loading (67.24%, w/w), high self-assembly stability, and high tumor selectivity. Compared with disulfide and thioether bonds, the trisulfide bond effectively promotes the self-assembly ability of doxorubicin homodimeric prodrugs, thereby improving the colloidal stability and in vivo fate of prodrug nanoassemblies. The trisulfide bond also shows higher glutathione sensitivity compared to the conventional disulfide bond, and this sensitivity enables efficient tumor-specific drug release. Therefore, trisulfide bond-bridged prodrug nanoassemblies exhibit high selective cytotoxicity on tumor cells compared with normal cells, notably reducing the systemic toxicity of doxorubicin. Our findings provide new insights into the design of advanced redox-sensitive nano-DDS for cancer therapy.

• Authors: Yinxian Yang, Bingjun Sun, Shiyi Zuo, Ximu Li, Shuang Zhou, Lingxiao Li, Cong Luo, Hongzhuo Liu, Maosheng Cheng, Yongjun Wang, Shujun Wang, Zhonggui He, Jin Sun
• Journal: Science advances (Sci Adv) Vol. 6 Issue 45 (11 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 33148644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Chemical References

• Disulfides
• Polymers
• Prodrugs
• Doxorubicin

Topics

• Cell Line, Tumor
• Disulfides (chemistry)
• Doxorubicin (pharmacology)
• Drug Delivery Systems
• Drug Liberation
• Nanoparticles (chemistry)
• Polymers
• Prodrugs (chemistry, pharmacology)