ROS-Activated Ratiometric Fluorescent Polymeric Nanoparticles for Self-Reporting Drug Delivery

Reactive oxygen species (ROS)-responsive theranostic nanomedicines have attracted wide interest in recent years because ROS stress is implicated in some pathological disorders such as inflammatory diseases and cancers. In this article, we report a kind of innovative ROS-responsive theranostic polymeric nanoparticles that are able to load hydrophobic drugs and to fluorescently self-report the in vitro or intracellular drug release under ROS triggering. The fluorescent nanoparticles were formed by amphiphilic block copolymers consisting of a poly­(ethylene glycol) (PEG) segment and an oxidation-responsive hydrophobic block. The copolymers with different hydrophobic block lengths were synthesized by the atom transfer radical polymerization of a phenylboronic ester-containing acrylic monomer with a small fraction of a ROS-activatable 1,8-naphthalimide-based fluorescent monomer, using PEG–Br as the macroinitiator. The copolymer nanoparticles were stable in neutral phosphate buffer but degraded upon H₂O₂ triggering, with the degradation rate depending on the hydrophobic block length and the concentration of H₂O₂. The degradation of nanoparticles was accompanied by a colorimetric change of the fluorophore from blue to green, which affords the nanoparticles the ability to detecting H₂O₂ by a ratiometric fluorescent approach. Moreover, the nanoparticles could encapsulate doxorubicin (DOX) and the H₂O₂-triggered DOX release was well associated with the change in ratiometric fluorescence. Confocal laser scanning microscope results reveal that the fluorescent nanoparticles were internalized into A549 cells through the endocytosis pathway. The ROS-stimulated degradation of the nanoparticles and intracellular DOX release and the fate of the degraded polymers could be monitored by ratiometric fluorescent imaging. Finally, the naked nanoparticles and the degradation products are cytocompatible, whereas the DOX-loaded ones exhibit concentration-dependent cytotoxicity. Of importance, the stimulation with exogenous H₂O₂ or lipopolysaccharide enhanced obviously the cell-killing capability of the DOX-loaded nanoparticles because of the ROS-enhanced intracellular DOX release.