Novel phage display-derived neuroblastoma-targeting peptides potentiate the effect of drug nanocarriers in preclinical settings.

Abstract

Molecular targeting of drug delivery nanocarriers is expected to improve their therapeutic index while decreasing their toxicity. Here we report the identification and characterization of novel peptide ligands specific for cells present in high-risk neuroblastoma (NB), a childhood tumor mostly refractory to current therapies. To isolate such targeting moieties, we performed combined in vitro/ex-vivo phage display screenings on NB cell lines and on tumors derived from orthotopic mouse models of human NB. By designing proper subtractive protocols, we identified phage clones specific either for the primary tumor, its metastases, or for their respective stromal components. Globally, we isolated 121 phage-displayed NB-binding peptides: 26 bound the primary tumor, 15 the metastatic mass, 57 and 23 their respective microenvironments. Of these, five phage clones were further validated for their specific binding ex-vivo to biopsies from stage IV NB patients and to NB tumors derived from mice. All five clones also targeted tumor cells and vasculature in vivo when injected into NB-bearing mice. Coupling of the corresponding targeting peptides with doxorubicin-loaded liposomes led to a significant inhibition in tumor volume and enhanced survival in preclinical NB models, thereby paving the way to their clinical development.

• Authors: Monica Loi, Daniela Di Paolo, Marco Soster, Chiara Brignole, Alice Bartolini, Laura Emionite, Jessica Sun, Pamela Becherini, Flavio Curnis, Andrea Petretto, Monica Sani, Alessandro Gori, Marco Milanese, Claudio Gambini, Renato Longhi, Michele Cilli, Theresa M Allen, Federico Bussolino, Wadih Arap, Renata Pasqualini, Angelo Corti, Mirco Ponzoni, Serena Marchiò, Fabio Pastorino
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 170 Issue 2 Pg. 233-41 (Sep 10 2013) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 23714122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Liposomes
• Peptides
• Doxorubicin

Topics

• Animals
• Cell Line, Tumor
• Cell Surface Display Techniques
• Cell Survival (drug effects)
• Cells, Cultured
• Doxorubicin (administration & dosage, chemistry)
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Liposomes
• Mice
• Mice, Nude
• Nanoparticles (administration & dosage, chemistry)
• Neuroblastoma (drug therapy, pathology)
• Peptides (administration & dosage, chemistry, pharmacokinetics)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays