Reactive oxygen species-responsive nanocomposite hydrogels for accurate drug delivery and localized PDT/PTT/chemo synergistic cancer therapy

Intratumor local drug delivery systems using injectable hydrogels have received considerable attention due to sustained, controllable drug delivery at target tumor sites and reduced adverse effects of systemic exposure to the drug. To maximize cancer therapeutic efficiency, this study focused on cytotoxic reactive oxygen species (ROS)cleavable injectable hydrogels that can more accurately control drug delivery as well as photodynamic therapy (PDT)/photothermal therapy (PTT) synergistic combination therapy. Thermo-responsive poly(N-isopropyl acrylamide) (PNIPAAm)-based injectable hydrogels were synthesized using a thioketal crosslinker vulnerable to bond breakage by ROS. In addition, PNIPAAm-based injectable nanocomposite hydrogels containing photo- sensitizer (PS)-conjugated gold nanorods (GNRs) as a photothermal factor and 1-methyltryptophan (1MT) as a model drug were prepared. PNIPAAm-based injectable nanocomposite hydrogel exhibited a lower critical solution temperature (LCST) in the range of 33.6-36.3 degrees C, allowing injection through a syringe at room temperature. However, a gel state was achieved through phase transition at a body temperature of 37 degrees C. ROS generation from PNIPAAm-based injectable nanocomposite hydrogel was controlled by adjusting the feed amount of PS-conjugated GNRs and the 670 nm laser intensity. These hydrogels crosslinked with ROS-cleavable thioketal crosslinker exhibited selective degradation and drug release behavior. In addition, a PNIPAAm-based injectable nanocomposite hydrogel containing GNRs as a photothermal factor and chlorin e6 (Ce6) as a PS showed a PDT/PTT synergistic effect upon laser irradiation. These results indicate that this ROS-sensitive nanocomposite hydrogel would be highly efficient both as an accurate drug delivery platform and as a combinational cancer therapeutic system of localized PDT and PTT.