The Superior Anticancer Effect of Reactive Oxygen Species-Responsive Paclitaxel Nanoparticles is Mediated Through Autophagic Cell Death.

Abstract

Paclitaxel (Ptx) is a first-line chemotherapeutic drug for advanced gastric cancer. However, the poor solubility of Ptx still limits its clinical application. Here, we designed a methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) (DSPE-PEG2000-TK-Ptx) nanoparticle loaded with "ROS sensitive" groups-thioketal (TK) to improve Ptx release in high ROS areas in cells. We evaluated the anticancer effect of the DSPE-PEG2000-TK-Ptx nanoparticles (Ptx-NPs) in the SGC-7901 gastric tumor cell line. The Ptx-NPs-treated group showed superior cytotoxicity to the same dose of free Ptx by MTT test and clonogenic assay. Autophagy inhibitor 3-MA protected cells from the cytotoxicity of Ptx in tumor cells. More autophagic cells were identified in the Ptx-NPs group via MDC/EB dual staining. NAC, an ROS inhibitor, inhibited cell autophagy induced by free Ptx or Ptx-NPs. SGC-7901 cells transfected with mCherry-EGFP-LC3II showed much brighter fluorescence in the Ptx-NPs group, while 3-MA markedly suppressed the fluorescence. Western blot verified the protein expression of autophagy, such as P62, Beclin 1 and LC3II. In this study, "ROS sensitive" conjugated DSPE-PEG2000-TK-Ptx nanoparticles with enhanced cancer-suppressive efficacy were produced. Ptx-NPs could be a promising antitumor agent for gastric cancer treatment with more efficiency and fewer side effects.