AUTHOR=Zhang Zhang , Feng Jintang , Zhang Tianzhu , Gao An , Sun Chunyang 

TITLE=Application of tumor pH/hypoxia-responsive nanoparticles for combined photodynamic therapy and hypoxia-activated chemotherapy

JOURNAL=Frontiers in Bioengineering and Biotechnology

VOLUME=11

YEAR=2023

URL=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2023.1197404

DOI=10.3389/fbioe.2023.1197404

ISSN=2296-4185

ABSTRACT=<p><bold>Introduction:</bold> Cancer selectivity, including targeted internalization and accelerated drug release in tumor cells, remains a major challenge for designing novel stimuli-responsive nanocarriers to promote therapeutic efficacy. The hypoxic microenvironment created by photodynamic therapy (PDT) is believed to play a critical role in chemoresistance.</p><p><bold>Methods:</bold> We construct dual-responsive carriers (<sup>DA</sup>NP<sub>CT</sub>) that encapsulate the photosensitizer chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) to enable efficient PDT and PDT-boosted hypoxia-activated chemotherapy.</p><p><bold>Results and discussion:</bold> Due to TAT masking, <sup>DA</sup>NP<sub>CT</sub> prolonged payload circulation in the bloodstream, and selective tumor cell uptake occurred via acidity-triggered TAT presentation. PDT was performed with a spatially controlled 660-nm laser to enable precise cell killing and exacerbate hypoxia. Hypoxia-responsive conversion of the hydrophobic NI moiety led to the disassembly of <sup>DA</sup>NP<sub>CT</sub>, facilitating TPZ release. TPZ was reduced to cytotoxic radicals under hypoxic conditions, contributing to the chemotherapeutic cascade. This work offers a sophisticated strategy for programmed chemo-PDT.</p>