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Int J Pharm. 2019 Mar 25;559:48-57. doi: 10.1016/j.ijpharm.2019.01.032. Epub 2019 Jan 21.

Enhanced anti-tumor efficiency of gemcitabine prodrug by FAPα-mediated activation.

Author information

1
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
2
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China; School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
3
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: wang-jc@bjmu.edu.cn.

Abstract

Gemcitabine (Gem) as an anti-cancer agent has been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and low therapeutic efficiency. To improve its anti-tumor activity, a novel FAPα enzyme-activated prodrug of Z-GP-Gem modified at 4-amino group of Gem was developed, which could effectively release parent Gem based on the specific cleavage via FAPα enzyme-activation in tumor microenvironment. Compared to Gem, the Z-GP-Gem prodrug exhibited significantly enhanced inhibition of both tumor growth and pulmonary metastasis in BALB/c mice bearing orthotopic breast 4T1 tumors. The Z-GP-Gem prodrug has a prolonged circulation time and a high tumor uptake based on the modification of Z-GP dipeptide at 4-amino group of Gem. These eventually caused a marked improvement in the systemic toxicity and the tumor growth inhibition in 4T1 cells. More interestingly, the unexpected depletion of tumor-associated fibroblast (TAF) was observed during the treatment of Z-GP-Gem prodrug in animal model. Therefore, these findings demonstrated that the FAPα-activated prodrug Z-GP-Gem would be a desirable approach for tumor therapy by intravenous administration.

KEYWORDS:

Antitumor activity; FAPα; Gemcitabine; Prodrug; Targeting

PMID:
30677483
DOI:
10.1016/j.ijpharm.2019.01.032
[Indexed for MEDLINE]

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