Enhancing the sensitization of neuroblastoma to radiotherapy by the construction of a dual-channel parallel free radicals nanoamplifier

Radiation therapy (RT) has emerged as one of the most promising anti-tumor strategies for neuroblastoma. Nevertheless, the special tumor microenvironment (TME), including hypoxic and GSH-overexpressed TME, often greatly restricts the RT outcome. In this study, we demonstrated a dual-channel parallel radicals nanoamplifier (ATO@PAE-PEG-AS1411/Fe3+). The nanoamplifier was shaped into a bilayer shell-core structure, in which atovaquone-loaded poly (beta-amino esters)-poly (ethylene glycol) (ATO@PAE-PEG) served as the core while Fe3+-absorbed AS1411 aptamer (AS1411/Fe3+) served as the shell. Taking advantage of the targeting ability of AS1411, ATO@PAE-PEG-AS1411/Fe3+ specifically accumulated in tumor cells, and then released ATO as well as Fe3+ in response to the acidic TME. The released ATO dramatically inhibited the mitochondrial respiration of tumor cells, thus sparing vast amounts of oxygen for the generation of free radicals during RT process, which was the first free radicals-amplifying pathway Meanwhile, the released Fe3+ could consume the tumor-overexpressed GSH through the redox reaction, thus effectively preserving the generated free radicals in RT process, which was the second free radicals-amplifying pathway. Taken together, our study demonstrates a dual-channel parallel free radicals-amplifying RT strategy, and it is expected this work will promote the clinical application prospects of RT treatment against neuroblastoma.