Combined targeting of perivascular and endothelial tumor cells enhances anti-tumor efficacy of liposomal chemotherapy in neuroblastoma.

Abstract

The therapeutic index of anti-cancer drugs is increased when encapsulating them in tumor-targeted liposomes. Liposome-entrapped doxorubicin (DXR), targeting the tumor vasculature marker, aminopeptidase N (APN), displayed enhanced anti-tumor effects and prolonged survival in human neuroblastoma (NB)-bearing mice. Here we exploited a peptide ligand of aminopeptidase A (APA), discovered by phage display technology for delivery of liposomal DXR to perivascular tumor cells. Immunohistochemistry, performed in NB-bearing mice, showed APA expression in the vascular wall of NB primary and metastatic lesions. APA-targeted peptides displayed specific binding to APA-transfected cells in vitro, and also accumulation in the tumor of NB-bearing mice. Consequently, novel, APA-targeted, DXR-liposomes were developed and in vivo proof-of-principle was established, alone and in combination with APN-targeted DXR-loaded liposomes, in NB-bearing mice. Mice receiving APA-targeted liposomal DXR exhibited an increased life span in comparison to control mice, but to a lesser extent relative to that in mice treated with APN-targeted formulation, moreover the greatest increase in TUNEL-positive tumor cells was observed in animals treated with APN-targeted formulations. Mice treated with a combination of APA- and APN-targeted, liposomal DXR had a significant increase in life span compared to each treatment administered separately. There was a significant increase in the level of apoptosis in the tumors of mice on the combination therapy, and a pronounced destruction of the tumor vasculature with nearly total ablation of endothelial cells and pericytes. The availability of novel ligands binding to additional tumor vasculature-associated antigens will allow the design of sophisticated combinations of ligand-targeted liposomal anti-cancer drugs.

• Authors: Monica Loi, Serena Marchiò, Pamela Becherini, Daniela Di Paolo, Marco Soster, Flavio Curnis, Chiara Brignole, Gabriella Pagnan, Patrizia Perri, Irene Caffa, Renato Longhi, Beatrice Nico, Federico Bussolino, Claudio Gambini, Domenico Ribatti, Michele Cilli, Wadih Arap, Renata Pasqualini, Theresa M Allen, Angelo Corti, Mirco Ponzoni, Fabio Pastorino
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 145 Issue 1 Pg. 66-73 (Jul 01 2010) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 20346382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier B.V. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Ligands
• Liposomes
• Peptides
• Doxorubicin
• CD13 Antigens
• Glutamyl Aminopeptidase

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, pharmacokinetics, therapeutic use)
• CD13 Antigens (biosynthesis, chemistry)
• Doxorubicin (administration & dosage, pharmacokinetics, therapeutic use)
• Drug Compounding
• Endothelial Cells (drug effects, metabolism, pathology)
• Female
• Glutamyl Aminopeptidase (biosynthesis, chemistry)
• Humans
• Immunohistochemistry
• Ligands
• Liposomes
• Mice
• Mice, Nude
• Neuroblastoma (blood supply, drug therapy, metabolism, pathology)
• Peptides (chemistry, metabolism)
• Protein Binding
• Xenograft Model Antitumor Assays