J Cancer 2020; 11(24):7184-7195. doi:10.7150/jca.47549

Research Paper

Design and biological evaluation of novel BF-30 analogs for the treatment of malignant melanoma

Jia Qi1,*, Weiwei Wang2,*, Wenying Lu2,*, Wei Chen2, Hui Sun1,✉, Anquan Shang3,✉

1. Department of dermatology, Nanjing Medical University Affiliated Wuxi Second hospital, Wuxi, Jiangsu, 214002, China.
2. Department of Laboratory Medicine, The Sixth People's hospital of Yancheng City, Yancheng, 224001, Jiangsu, China.
3. Department of Laboratory Medicine, Tongji hospital of Tongji University, Shanghai 200065, Shanghai, China.
*The authors contributed equally to this work.

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Qi J, Wang W, Lu W, Chen W, Sun H, Shang A. Design and biological evaluation of novel BF-30 analogs for the treatment of malignant melanoma. J Cancer 2020; 11(24):7184-7195. doi:10.7150/jca.47549. Available from https://www.jcancer.org/v11p7184.htm

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Aims: To evaluate anti-tumour effects and mechanism of novel BF-30 derivative via cell-based assays and melanoma-bearing model mice.

Main methods: BF-30 derivatives were designed by fusing heptapeptide-palmitic tags to native BF-30 via a protease-cleavable linker and prepared by F-moc solid-phase synthesis. Albumin binding affinity test and in vitro control-released assay were performed to screen these BF-30 derivatives and explore the mechanism of anti-tumour effects. The selected BF-30 derivative was further subjected to the preclinical efficacy study and chronic evaluation of anti-tumour effects melanoma-bearing model mice.

Key findings: Twenty-one BF-30 derivatives, termed LBF-1 to LBF-21, were obtained with high purity and accurate molecular weight. Surface plasmon resonance (SPR) measurements, plasma stability test and in vitro control-released assay all showed that LBF-14 exerted better druggability compared with the others. Moreover, LBF-14 was proved to inhibit the proliferation of B16F10 melanoma cell by disrupting the cytoplasmic membrane and binding to genomic DNA to prevent transcription. Furthermore, half-life of intact LBF-14 and released BF-30 in rhesus monkeys were approximately 120.9 h and 136.4 h, respectively, after a single subcutaneous injection of 0.9 mg/kg LBF-14. In addition, chronic treatment of LBF-14 significantly suppressed melanoma growth and improved the survival rate of B16F10-bearing mice with the observed inhibition of 63.5% for 0.3mg/kg and 91.5% for 0.9 mg/kg. Furthermore, results of H&E staining prove that chronic treatment of LBF-30 effectively suppressed metastasis and invasion of B16F10 cells.

Significance: LBF-14 holds potential to be developed as a promising once-weekly candidate for the treatment of malignant melanoma.

Keywords: Cathelicidin-BF, controlled-release, albumin binding, thrombin, melanoma