Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy

Bingjun Sun,Mengran Guo,Qin Chen,Xuanbo Zhang,Shiyi Zuo,Menglin Wang,Jin Sun,Wenqian Yang,Pengyu Chen,Han Yu,Qiming Kan,Cong Luo,Mengchi Sun,Haotian Zhang,Zhonggui He,Yongjun Wang

doi:10.1038/s41467-019-11193-x

Abstract

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.

Highlights

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione
The bond angles/dihedral angles of sulfur/selenium-based linkages might influence the self-assembly performance and colloidal stability of prodrug nanoassemblies; (ii) the difference in redox-responsivity between sulfur/selenium bonds could have remarkable influence on the drug release characteristics and cytotoxicity of prodrug nanoassemblies[27,28,29]; (iii) several selenium-containing molecules have been reported with the unique ability to produce reactive oxygen species (ROS) and induce apoptosis of tumor cells[17,30,31,32], which might further affect the cytotoxicity and antitumor efficiency of prodrug nanoassemblies
We proposed that the distinct properties of sulfur/selenium bonds might significantly affect the drug delivery characteristics of prodrug nanoassemblies, including self-assembly performance, redox-responsive drug release and antitumor efficiency

Summary

Introduction

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. We proposed that the distinct properties of sulfur/selenium bonds might significantly affect the drug delivery characteristics of prodrug nanoassemblies, including self-assembly performance, redox-responsive drug release and antitumor efficiency.

Results

Conclusion