Ditelluride-bridged, ROS-responsive nanoparticles based on carboxymethyl chitosan for potentiating doxorubicin chemotherapy

Abstract Although chemotherapy remains a cornerstone of oncological treatment, its clinical application is severely hindered by the systemic toxicity and poor targeting efficiency inherent in conventional drug delivery systems. Given the relatively low levels of reactive oxygen species (ROS) in pathological tissues (<100 μM), there is an urgent need to develop stimuli-responsive carriers with superior sensitivity. In this study, we developed ditelluride-bridged carboxymethyl chitosan nanoparticles (DTeC NPs) as an innovative, ROS-triggered doxorubicin (DOX) release platform, using disulfide-crosslinked nanoparticles (DSC NPs) as a comparative control. Both nanocarriers exhibited a uniform particle size of approximately 200 nm and achieved high drug loading (∼25%) via electrostatic interactions with the polysaccharide backbone. Owing to the exceptional sensitivity of ditelluride bonds to oxidative environments, DTeC NPs demonstrated significantly accelerated degradation and drug release; notably, the cumulative DOX release reached 98.1% within 48 h in the presence of 100 μM H 2 O 2 . Furthermore, in vitro assays confirmed that DTeC/DOX NPs effectively enhanced cellular uptake. At a DOX concentration of 8 μg Ml −1 , DTeC/DOX NPs reduced the viability of HepG2 and H22 cells to 27.4% and 33.9%, respectively, demonstrating significantly higher cytotoxicity compared to DSC/DOX NPs (35.9% for HepG2 and 45.8% for H22). In vivo studies further revealed that DTeC/DOX NPs achieved a tumor growth inhibition (TGI) rate of 72.29% in H22 tumor-bearing mice, markedly outperforming both free DOX (42.19%) and the disulfide-crosslinked control (60.81%). In summary, these findings underscore the immense potential of the ditelluride-crosslinking strategy for enhancing the precision and therapeutic efficacy of cancer chemotherapy.