Reactive oxygen species-activatable self-amplifying Watson-Crick base pairing-inspired supramolecular nanoprodrug for tumor-specific therapy

Xiaoyu Xu; Zishan Zeng; Xin Ding; Ting Shan; Qiuxing Liu; Meixu Chen; Jie Chen; Meng Xia; Yuanfeng He; Zeqian Huang; Yanjuan Huang; Chunshun Zhao

doi:10.1016/j.biomaterials.2021.121128

Reactive oxygen species-activatable self-amplifying Watson-Crick base pairing-inspired supramolecular nanoprodrug for tumor-specific therapy

Biomaterials. 2021 Oct:277:121128. doi: 10.1016/j.biomaterials.2021.121128. Epub 2021 Sep 11.

Authors

Xiaoyu Xu¹, Zishan Zeng¹, Xin Ding¹, Ting Shan¹, Qiuxing Liu¹, Meixu Chen¹, Jie Chen¹, Meng Xia¹, Yuanfeng He¹, Zeqian Huang¹, Yanjuan Huang¹, Chunshun Zhao²

Affiliations

¹ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
² School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China. Electronic address: zhaocs@mail.sysu.edu.cn.

PMID: 34537502
DOI: 10.1016/j.biomaterials.2021.121128

Abstract

Intratumoral upregulated reactive oxygen species (ROS) has been extensively exploited as exclusive stimulus to activate drug release for tumor-specific therapy. However, insufficient endogenous ROS and tumor heterogeneity severely restrict clinical translation of current ROS-responsive drug delivery systems. Herein, a tailored ROS-activatable self-amplifying supramolecular nanoprodrug was developed for reinforced ROS-responsiveness and highly selective antitumor therapy. A novel ROS-cleavable CA-based thioacetal linker CASOH was synthesized with ROS generator cinnamaldehyde (CA) incorporated into its molecular structure, to skillfully realize self-amplifying positive feedback loop of "ROS-activated CA release with CA-induced ROS regeneration". CASOH was modified with a cytosine analogue gemcitabine (GEM) to obtain ROS-activatable self-immolative prodrug CAG, which could be selectively activated in tumor cells and further achieve self-boosting "snowballing" activation via ROS compensation, while keep inactive in normal cells. Through Watson-Crick nucleobase pairing (G≡C)-like hydrogen bonds, CAG efficiently crosslinked with a matched guanine-rich acyclovir-modified hyaluronic acid conjugate HA-ACV, to self-assemble into pH/ROS dual-responsive supramolecular nanoprodrug HCAG. With high stability, beneficial tumor targeting capacity and pH/ROS-responsiveness, HCAG nanoformulation exhibited remarkable in vivo antitumor efficacy with minimal systemic toxicity. Based on unique tumor-specific self-amplifying prodrug activation and Watson-Crick base pairing-inspired supramolecular self-assembly, this study provides an inspirational strategy of exploiting novel ROS-responsive nanoplatform with reinforced responsiveness and specificity for future clinical translation.

Keywords: Hydrogen bonds; Reactive oxygen species; Self-amplifying; Supramolecular nanoprodrug; Tumor-specific therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Drug Delivery Systems
Drug Liberation
Nanoparticles*
Reactive Oxygen Species

Substances

Reactive Oxygen Species