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Gemcitabine (Gem) is a standard first-line treatment for pancreatic cancer (PC).However,its chemotherapeutic efficacy is hampered by various limitations such as short half-life,metabolic inactivation,and lack of tumor localizing.We previously synthesized a lipophilic Gem derivative (Gem formyl hexadecyl ester,GemC16) that exhibited improved antitumor activity in vitro.In this study,a target ligand N,N-dimethyl-1,3-propanediamine was conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[hydroxyl succinimidyl (polyethylene glycol-2000)] (DSPE-PEG-NHS) to form DSPE-PEG-2N.Then,pancreas-targeting liposomes (2N-LPs) were prepared using the film dispersion-ultrasonic method.GemC16-loaded 2N-LPs displayed near-spherical shapes with an average size distribution of 157.2 nm (polydispersity index (PDI) =0.201).The encapsulation efficiency of GemC16 was up to 97.3％ with a loading capacity of 8.9％.In human PC cell line (BxPC-3) and rat pancreatic acinar cell line (AR42J),cellular uptake of 2N-LPs was significantly enhanced compared with that of unmodified PEG-LPs.2N-LPs exhibited more potent in vitro cytotoxicity against BxPC-3 and AR42J cell lines than PEG-LPs.After systemic administration in mice,2N-LPs remarkably increased drug distribution in the pancreas.in an orthotopic tumor mouse model of PC,GemC16-bearing liposomes were more effective in preventing tumor growth than free GemC16.Among these treatments,2N-LPs showed the best curative effect.Together,2N-LPs represent a promising nanocarrier to achieve pancreas-targeting drug delivery,and this work would provide new ideas for the chemotherapy of PC.