Theranostics 2018; 8(8):2094-2106. doi:10.7150/thno.22069

Research Paper

Development of a novel albumin-based and maleimidopropionic acid-conjugated peptide with prolonged half-life and increased in vivo anti-tumor efficacy

Junnan Feng1, Chuanke Zhao1✉, Lixin Wang1, Like Qu1, Hua Zhu2, Zhi Yang2, Guo An3, Huifang Tian4, Chengchao Shou1✉

1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China
2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing 100142, China.
4. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Central Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China.

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Citation:
Feng J, Zhao C, Wang L, Qu L, Zhu H, Yang Z, An G, Tian H, Shou C. Development of a novel albumin-based and maleimidopropionic acid-conjugated peptide with prolonged half-life and increased in vivo anti-tumor efficacy. Theranostics 2018; 8(8):2094-2106. doi:10.7150/thno.22069. Available from http://www.thno.org/v08p2094.htm

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Abstract

Angiogenesis plays a critical role in tumor aggressiveness, and a lot of anti-angiogenic agents have been used in clinical therapy. The therapeutic efficacy of peptides are generally restricted by the short in vivo life-time, thus, we were interested in developing a novel albumin-based and maleimidopropionic acid-conjugated peptide to prolong the half-life and improve the anti-tumor effect.

Methods: We developed a peptide F56 with a maleimidopropionic acid (MPA) at the C-terminal (denoted as F56-CM), which allows immediate and irreversible conjugation with serum albumin. Biological property and anti-tumor activity of F56-CM were evaluated in vitro and in vivo.

Results: We showed that F56-CM reduced migration and tube formation of endothelial cells in vitro and inhibited the generation of subintestinal vessels (SIV) in zebrafish embryos in vivo. F56-CM inhibited vascular endothelial growth factor (VEGF) induced phosphorylation of VEGFR1 and activation of the PI3K-AKT axis. Furthermore, F56-CM rapidly conjugated with albumin upon intravenous injection and extended the biological half-life of F56 from 0.4249 h to 6.967 h in rats. Compared with F56, F56-CM exhibited stronger anti-tumor activity on both BGC-823 gastric cancer and HT-29 colon cancer xenografts in nude mice, and the statistical difference was remarkable. More significantly, the efficacy of F56-CM inhibiting lung metastasis of BGC-823 cells was also better than that of F56. The inhibition rates were 62.1% and 78.9% for F56 and F56-CM respectively when administrated every day, and 43.8% and 63.1% when administrated every four days at equal dose.

Conclusions: Taken together, our results demonstrated that F56-CM has considerable potential for cancer therapy.

Keywords: F56, MPA, albumin conjugate, anti-tumor, VEGFR1