Polyhedral oligomeric silsesquioxane (POSS)-based hybrid nanocomposite for synergistic chemo-photothermal therapy against pancreatic cancer

Pancreatic cancer is highly malignant with a poor prognosis. Gemcitabine-based chemotherapy is the first-line treatment for pancreatic cancer; however, its clinical outcomes remain unsatisfactory due to drug resistance and side effects. In this study, we developed and characterized a novel polyhedral oligomeric silsesquioxane (POSS)-based nanoplatform (GEM-POSS-SQ), where the photothermal agent squaraine (SQ) and chemotherapeutic drug gemcitabine (GEM) were grafted into POSS via an efficient click chemistry method for combination therapy. The resultant GEM-POSS-SQ nanoparticles (NPs) effectively eliminated the aggregation of SQ and enhanced the photothermal performance in vitro and in vivo. Cell viability and apoptosis assays showed that GEM-POSS-SQ NPs exhibited a significant synergistic chemo-photothermal effect, especially in chemoresistant PANC-1 pancreatic cancer cells. Confocal laser scanning microscopy revealed near infrared (NIR)-triggered cell membrane disruption and GEM-mediated nuclear damage caused by GEM-POSS-SQ NPs. Intratumoral application of GEM-POSS-SQ NPs under NIR irradiation greatly inhibited tumor growth in PANC-1 tumor-bearing mice, with a higher proportion of TUNEL-positive cells and a lower proportion of Ki-67-positive cells observed in isolated tumor tissue. Importantly, no noticeable side effects were observed in the mice. The as-prepared GEM-POSS-SQ nanoparticles can serve as an alternative strategy to fight pancreatic cancer and can also be exploited to treat other cancers.