Hypoxia-responsive nanomedicine to overcome tumor microenvironment-mediated resistance to chemo-photodynamic therapy

Hypoxia is a feature of solid tumors that greatly hinders cancer treatment. Here, we developed hypoxiaresponsive nanoparticles (NPs) that selectively release chlorin e6 (Ce6) and paclitaxel (PTX) under hypoxic conditions. To prepare the hypoxia-responsive NPs, PTX-loaded HSA NPs (PHNPs) were functionalized with 4,40-azodianiline (Azo) as a linker for the PHNPs and Ce6 (CA/PHNPs). The CA/PHNPs were then functionalized with RGD-conjugated poly(ethylene glycol) (RP/CA/PHNPs). The azo group (-N]N-) present in Azo was reductively cleaved under hypoxic conditions to release Ce6 and PTX. The release of Ce6 due to azo cleavage under hypoxia resulted in a uniform distribution of Ce6 within HeLa cells and spheroids, enhancing antitumor activity even in a hypoxic environment. The RP/CA/PHNPs also showed excellent antitumor effects in a HeLa cell xenograft mouse model. Thus, this strategy for controlling the drug distribution within a hypoxic tumor microenvironment (TME) potentially represents a very effective strategy for the removal of solid tumors with a hypoxic TME by improving the efficiency of photodynamic therapy and chemotherapy. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).