Redox-responsive nanoparticles having a diselenide linkage were synthesized to target pulmonary metastasis of cancer cells. Methoxy poly (ethylene glycol)-grafted chitosan (ChitoPEG) was crosslinked using selenocystine-acetyl histidine (Ac-histidine) conjugates (ChitoPEGse) for stimuli-responsive delivery of piperlongumine (PL). ChitoPEGse nanoparticles swelled in an acidic environment and became partially disintegrated in the presence of H2O2 10mM, resulting in an increase of particle size and in a size distribution having multimodal pattern. PL release increased under acidic conditions and in the presence of H2O2. Uptake of ChitoPEGse nanoparticles (PL NP) showed similar anticancer activity in vitro against A549 and CT26 cells compared to PL itself. PL NP showed superior anticancer and anti-metastatic activity in an in vivo CT26 cell pulmonary metastasis mouse model. Furthermore, an immunofluorescence imaging study demonstrated that PL NP conjugates were specifically delivered to the tumor mass in the lung. Conclusively, ChitoPEGse nanoparticles were able to be delivered and released to cancer cells with an acidic- or redox state-sensitive manner and then were selectively targeted to pulmonary metastasis of cancer cells since ChitoPEGse nanoparticles have both pH- and redox-responsiveness.
