A NAG-guided nano-delivery system for redox-and pH-triggered intracellularly sequential drug release in cancer cells

Abstract

Aim: Sequential treatment with paclitaxel (PTXL) and gemcitabine (GEM) is considered clinically beneficial for non-small-cell lung cancer. This study aimed to investigate the effectiveness of a nano-system capable of sequential release of PTXL and GEM within cancer cells. Methods: PTXL-ss-poly(6-O-methacryloyl-d-galactopyranose)-GEM (PTXL-ss-PMAGPGEM) was designed by conjugating PMAGP with PTXL via disulfide bonds (-ss-), while GEM via succinic anhydride (PTXL:GEM=1:3). An amphiphilic block copolymer N-acetyld-glucosamine(NAG)-poly(styrene-alt-maleic anhydride)58-b-polystyrene130 acted as a targeting moiety and emulsifier in formation of nanostructures (NLCs). Results: The PTXL-ss-PMAGP-GEM/NAG NLCs (119.6 nm) provided a sequential in vitro release of, first PTXL (redox-triggered), then GEM (pH-triggered). The redox-and pHsensitive NLCs readily distributed homogenously in the cytoplasm. NAG augmented the uptake of NLCs by the cancer cells and tumor accumulation. PTXL-ss-PMAGP-GEM/NAG NLCs exhibited synergistic cytotoxicity in vitro and strongest antitumor effects in tumorbearing mice compared to NLCs lacking pH/redox sensitivities or free drug combination. Conclusion: This study demonstrated the abilities of PTXL-ss-PMAGP-GEM/NAG NLCs to achieve synergistic antitumor effect by targeted intracellularly sequential drug release.