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A novel gemcitabine derivative-loaded liposome with great pancreas-targeting ability

Abstract

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.

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Acknowledgements

We acknowledge the financial support of the Science & Technology Department of Sichuan Province (No. 2018SZ0012, No. 2019YJ0372), the Collaborative Innovation Center of Sichuan for Elderly Care and Health (No. YLZBZ1808), and Chengdu Medical College (No. CYZ17-07).

Author information

ZRZ and YCZ conceived and designed the study. PWL performed the experiments and generated and analyzed the data. SL and LYX helped with the animal and cell studies, and SL and LW helped with the synthesis studies. BLT assisted in data analysis. YCZ wrote the original manuscript, and ZRZ helped with manuscript editing.

Correspondence to Ying-chun Zeng.

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The authors declare no competing interests.

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Keywords

  • pancreatic cancer
  • gemcitabine derivative
  • propanediamine
  • liposomes
  • targeted drug delivery
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