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

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...

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Bibliographic Details
Published in:Acta pharmacologica Sinica 2019-11, Vol.40 (11), p.1448-1456
Main Authors: Li, Pei-Wen, Luo, Shi, Xiao, Lin-Yu, Tian, Bo-le, Wang, Li, Zhang, Zhi-Rong, Zeng, Ying-Chun
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - therapeutic use
Antitumor activity
Biotechnology
Cell Line, Tumor
Chemotherapy
Cytotoxicity
Deoxycytidine - administration & dosage
Deoxycytidine - analogs & derivatives
Deoxycytidine - therapeutic use
Diamines - chemical synthesis
Diamines - chemistry
Diamines - toxicity
Drug Carriers - chemical synthesis
Drug Carriers - chemistry
Drug Carriers - toxicity
Drug delivery
Drug Delivery Systems - methods
Gemcitabine
Inactivation
Lipophilic
Liposomes
Liposomes - chemical synthesis
Liposomes - chemistry
Liposomes - toxicity
Mice, Inbred C57BL
Pancreas
Pancreas - metabolism
Pancreas - pathology
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - pathology
Phosphatidylethanolamines - chemical synthesis
Phosphatidylethanolamines - chemistry
Phosphatidylethanolamines - toxicity
Polydispersity
Polyethylene glycol
Polyethylene Glycols - chemical synthesis
Polyethylene Glycols - chemistry
Polyethylene Glycols - toxicity
Size distribution
Ultrasonic testing
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Summary: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.
ISSN:1671-4083
1745-7254
DOI:10.1038/s41401-019-0227-7