Conotoxin-derived biomimetic coiled cone-shaped peptide as ligand for selective nanodelivery to norepinephrine transporter-expressing neuroblastoma cells

Selective drug delivery is an emerging powerful strategy, which promises efficient and safer neuroblas-toma treatment in contrast to conventional therapeutic modalities. Herein, we present a newly designed apoferritin nanovehicle loaded with ellipticine and decorated with conotoxin-derived biomimetic pep -tide YKL-6 (sequence: YKLYKLYKLYKLYKLYKLC) to target the norepinephrine transporter (hNET), which is highly expressed on neuroblastoma cells membrane. The peptide forms a coiled cone-shape forming anti-parallel beta sheets in aggregation in vitro . Molecular docking analysis suggests electrostatic interaction mediated by lysine residues against negatively charged residues of the hNET. The assembled nanovehicles show optimal biocompatibility in healthy epithelial cells and ability to deliver ellipticine into neuroblas-toma cells (UKF-NB-4 and SH-SY5Y). In our analyses, we have excluded hNET-mediated endocytosis as an uptake mechanism and demonstrated the ellipticine-triggered anti-proliferative mechanisms in neurob-lastoma cells via downregulation of Bcl-2, survivin and N-myc. Finally, we present a selective inhibition of neuroblastoma growth and metastasis in vivo in an ex ovo and in ovo chicken chorioallantoic mem-brane assay. Overall, these findings demonstrate a great leap forward in the design of biomimetic homing peptides towards possible application in neuroblastoma nanomedicine.(c) 2022 Elsevier Ltd. All rights reserved.