Blood circulation stable doxorubicin prodrug nanoparticles containing hydrazone and thioketal moieties for antitumor chemotherapy

Prodrug nanoparticles with cleavable moieties sensitive to intracellular stimuli have drawn great attention on cancer chemotherapy. Herein, a reactive oxygen species (ROS)-responsive doxorubicin prodrug mPEG-Phe-TK-Phe-hyd-DOX was synthesized, in which hydrophilic methoxy poly(ethylene glycol) (mPEG) and hydrophobic anticancer drug doxorubicin (DOX) were conjugated with hydrazone (hyd) and ROS-responsive thioketal (TK) moieties. The ROS-responsiveness of prodrug was confirmed by proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). Unexpectedly, the results of in vitro drug release indicated that the hydrazone bond of prodrug nanoparticles was insensitive to pH, which may be due to the strong hydrophobicity, π-π interactions and cation-π interactions jointly inhibited the hydrolysis of hydrazone bonds under acidic conditions. The cellular uptake and in vitro anticancer study showed that ROS-responsive prodrug nanoparticles exhibited faster cellular uptake and better anticancer efficacy. The in vivo experiments showed that the ROS-responsive prodrug nanoparticles had comparable antitumor efficacy with free anticancer drug DOX and reduced organ toxicity. Our results provide novel idea of successfully design multi-stimuli-responsive nano-drug carrier.