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

Abstract

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.

Anticancer activities of natural antimicrobial peptides from animals

“…In vivo experiments, BF-30 obviously inhibited melanoma development in B16F10 tumor-bearing mice without adverse reactions occurring ( Wang et al, 2013 ). In addition, Qi et al (2020) designed a BF-30 derivative, LBF-14, which exhibited significant anti-melanoma action through disrupting the cell membrane, and then binding to the genomic DNA to suppress the migration and angiogenesis of melanoma cells.…”

Recent advances in the therapeutic potential of cathelicidins

“…The molecule was also tested in a mouse cancer model, showing a significant suppression in melanoma growth and improved survival rates of B16F10-bearing mice. Cytotoxicity was analyzed in vivo in rhesus monkeys and showed that the modified version was less toxic and presented an increased half-live in comparison with the native AMP ( Qi et al, 2020 ).…”

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“…The molecule was also tested in a mouse cancer model, showing a significant suppression in melanoma growth and improved survival rates of B16F10-bearing mice. Cytotoxicity was analyzed in vivo in rhesus monkeys and showed that the modified version was less toxic and presented an increased half-live in comparison with the native AMP (Qi et al, 2020).…”