Stepwise-activatable hypoxia triggered nanocarrier-based photodynamic therapy for effective synergistic bioreductive chemotherapy

Tumor cell populations are highly heterogeneous, which limit the homogeneous distribution and optimal delivery of nanomedicines, thereby inducing insufficient therapeutic benefits. We develop tumor microenvironment activatable and external stimuli-responsive drug delivery system ((TAT+Azo)NPs), which can improve photodynamic therapy (PDT) induced bioreductive chemotherapy in different tumor cells both proximal and distal to vessels. The TAT peptide on the surface of (TAT+Azo)NPs can both facilitate the cell uptake and the penetration of (TAT+Azo)NPs owing to its responsiveness to tumor stimuli pH. (TAT+Azo)NPs can keep the cargoes (photo- sensitizer chlorine e6 (Ce6) and hypoxia activatable prodrug tirapazamine (TPZ)) and highly accumulate within tumor cells proximity and distal to vessels. The Azo-benzene bonds as the linkers between amphiphilic polymers remain stable under normoxia, but quite break at hypoxic conditions. Upon external laser irradiation, the intratumoral fate of (TAT+Azo)NPs involved two processes: 1) (TAT+Azo)NPs achieve efficient PDT on tumor cells proximal to vessel, since sufficient O-2 supply; and 2) PDT-induced more hypoxia can trigger TPZ release by breakage of Azo-benzene bond as well as accelerate the activation of TPZ for improvingcombination therapy efficacy in tumor cells distal to vessel. This study gives a direction for the development of stepwise-activatable hypoxia triggered nanosystem for PDT-induced bioreductive chemotherapy for tumor cells in different distances to vessels.