A highly tumor-specific light-triggerable drug carrier responds to hypoxic tumor conditions for effective tumor treatment

Light-triggered drug delivery is among the most investigated stimulus-response strategies and has been widely explored in cancer treatment. However, the limited specificity of light-triggered drug delivery reduces the therapeutic efficacy and causes considerable undesirable side effects. In this work, we demonstrate a highly tumor-specific light-triggerable drug carrier (H-LTDC) induced by a combination of internal (i.e., tumor hypoxia) and external stimuli (i.e., light). The doxorubicin (DOX)-loaded H-LTDC was self-assembled from type-1-reactive oxygen species (ROS_type1)-mediated degradable chondroitin sulfate (CS) conjugated with a photosensitizer (PS), Pheophorbide-a, which has a spherical shape and a uniform size distribution. Under hypoxic conditions, ROS_Type1 was mainly generated due to the electron-rich sulfate groups in the polysaccharide backbone. The ROS_type1 generated by H-LTDC allowed laser-triggered drug release at low oxygen concentrations. From the in vitro cytotoxicity tests with colon cancer cells (HCT-116), under laser irradiation, DOX-loaded H-LTDCs showed higher toxicity under hypoxic conditions than that under normoxic conditions. In vivo and ex vivo biodistribution studies demonstrated that H-LTDCs selectively accumulated in the tumor tissues. As a result, drug-loaded H-LTDCs exhibited high anti-tumor activity in vivo. Overall, we believe that this approach could represent a promising platform for the treatment of tumor and hypoxia-associated diseases without undesirable side effects.