Prodrug nanoassemblies bridged by Mono-/Di-/Tri-sulfide bonds: Exploration is for going further

Sulfur bonds, including thioether bond and disulfide bond, have been widely used to develop tumor redox-responsive drug delivery systems. Recently, trisulfide bond was also introduced into the construction of prodrug nanoassemblies. However, the integrated effects of these sulfur bonds on prodrug nanoassemblies remain elusive. Here, three paclitaxel homodimeric prodrugs are synthesized using thioether bond, disulfide bond or trisulfide bond as linkages. Interestingly, the sulfur bonds significantly changed the molecular assembly of prodrugs, thereby influencing the colloidal stability and in vivo destiny of prodrug nanoassemblies. More importantly, the trisulfide bond is found to be a novel redox dual-sensitive linkage, and the responsive mechanism is illustrated. The differences of thioether/disulfide/trisulfide bond are investigated in-depth, and their effect on the antitumor efficacy of prodrug nanoassemblies is also clarified. Our findings provide deep insights into the impacts of sulfur bonds on prodrug nanoassemblies, and highlight the potential of trisulfide bond for the development of redox dual-responsive nanomedicines.