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+AzoNPs), 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+AzoNPs can both facilitate the cell uptake and the penetration of TAT+AzoNPs, owing to its responsiveness to
tumor stimuli pH. TAT+AzoNPs can keep the cargoes (
photosensitizer 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+AzoNPs involved two processes: 1) TAT+AzoNPs achieve efficient
PDT on
tumor cells proximal to vessel, since sufficient O2 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.