Logic gate nanocarriers based on pH and ROS dual sensitive poly(orthoester-thioether) for enhanced anticancer drug delivery

ABSTRACT The traditional poly(orthoesters) nanoparticles degrade very slowly at acidic pH due to surface erosion. While the amphiphilic poly(orthoesters) micelles lack stability. Therefore, to improve the stability of carriers and drug release capacity, we synthesized a new type of pH and ROS dual responsive poly(orthoester-thioether) (PSOE) with orthoester and thioether in main chain to build logic gate nanoparticles by transesterification between an orthoester and a diol. The self-assembled PSOE nanospheres (PSOE NPs) kept stable under physiological condition, while degraded rapidly in the presence of hydrogen peroxide and acidic pH because hydrophobic-to-hydrophilic transition upon stimulation by hydrogen peroxide, resulted in rapid degradation of orthoester. The drug release profiles demonstrated that doxorubicin release from PSOE NPs was significantly accelerated under mildly acidic and ROS condition. In vitro cell experiments revealed that DOX-loaded PSOE NPs exhibited efficient antitumor effect against monolayer cells and three-dimensional multicellular spheroids. Therefore, pH and ROS dual responsive PSOE NPs may be a promising candidate for efficient drug delivery.