This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pastorino, F. Articles by Ponzoni, M. Search for Related Content PubMed PubMed Citation Articles by Pastorino, F. Articles by Ponzoni, M.

Targeting Liposomal Chemotherapy via Both Tumor Cell–Specific and Tumor Vasculature–Specific Ligands Potentiates Therapeutic Efficacy

¹ Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy; ² Department of Human Anatomy, University of Bari, Bari, Italy; ³ Animal Research Facility, Istituto Tumori, Genoa, Italy; ⁴ Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche; ⁵ Immunobiotechnology Unit, San Raffaele Institute, Milan, Italy; and ⁶ Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada

Requests for reprints: Mirco Ponzoni, Differentiation Therapy Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16148, Genoa, Italy. Phone: 39-10-563-6342; Fax: 39-10-377-9820; E-mail: mircoponzoni{at}ospedale-gaslini.ge.it.

Neuroblastoma, the most common solid tumor of infancy derived from the sympathetic nervous system, continues to present a formidable clinical challenge. Sterically stabilized immunoliposomes (SIL) have been shown to enhance the selective localization of entrapped drugs to solid tumors, with improvements in therapeutic indices. We showed that SIL loaded with doxorubicin (DXR) and targeted to the disialoganglioside receptor GD₂ [aGD₂-SIL(DXR)] led to a selective inhibition of the metastatic growth of experimental models of human neuroblastoma. By coupling NGR peptides that target the angiogenic endothelial cell marker aminopeptidase N to the surface of DXR-loaded liposomes [NGR-SL(DXR)], we obtained tumor regression, pronounced destruction of the tumor vasculature, and prolonged survival of orthotopic neuroblastoma xenografts. Here, we showed good liposome stability, long circulation times, and enhanced time-dependent tumor accumulation of both the carrier and the drug. Antivascular effects against animal models of lung and ovarian cancer were shown for formulations of NGR-SL(DXR). In the chick embryo chorioallantoic assay, NGR-SL(DXR) substantially reduced the angiogenic potential of various neuroblastoma xenografts, with synergistic inhibition observed for the combination of NGR-SL(DXR) with aGD₂-SIL(DXR). A significant improvement in antitumor effects was seen in neuroblastoma-bearing animal models when treated with the combined formulations compared with control mice or mice treated with either tumor- or vascular-targeted liposomal formulations, administered separately. The combined treatment resulted in a dramatic inhibition of tumor endothelial cell density. Long-term survivors were obtained only in animals treated with the combined tumor- and vascular-targeted formulations, confirming the pivotal role of combination therapies in treating aggressive metastatic neuroblastoma. (Cancer Res 2006; 66(20): 10073-82)

This article has been cited by other articles:

				J. Hamzah, J. G. Altin, T. Herringson, C. R. Parish, G. J. Hammerling, H. O'Donoghue, and R. Ganss Targeted Liposomal Delivery of TLR9 Ligands Activates Spontaneous Antitumor Immunity in an Autochthonous Cancer Model J. Immunol., July 15, 2009; 183(2): 1091 - 1098. [Abstract] [Full Text] [PDF]

				F. Pastorino, D. Di Paolo, F. Piccardi, B. Nico, D. Ribatti, A. Daga, G. Baio, C. E. Neumaier, C. Brignole, M. Loi, et al. Enhanced Antitumor Efficacy of Clinical-Grade Vasculature-Targeted Liposomal Doxorubicin Clin. Cancer Res., November 15, 2008; 14(22): 7320 - 7329. [Abstract] [Full Text] [PDF]

				A. Corti, F. Curnis, W. Arap, and R. Pasqualini The neovasculature homing motif NGR: more than meets the eye Blood, October 1, 2008; 112(7): 2628 - 2635. [Abstract] [Full Text] [PDF]

				F. Curnis, A. Sacchi, A. Gasparri, R. Longhi, A. Bachi, C. Doglioni, C. Bordignon, C. Traversari, G.-P. Rizzardi, and A. Corti Isoaspartate-Glycine-Arginine: A New Tumor Vasculature-Targeting Motif Cancer Res., September 1, 2008; 68(17): 7073 - 7082. [Abstract] [Full Text] [PDF]

				A. Lo, C.-T. Lin, and H.-C. Wu Hepatocellular carcinoma cell-specific peptide ligand for targeted drug delivery Mol. Cancer Ther., March 1, 2008; 7(3): 579 - 589. [Abstract] [Full Text] [PDF]

				M. Wickstrom, J. I. Johnsen, F. Ponthan, L. Segerstrom, B. Sveinbjornsson, M. Lindskog, H. Lovborg, K. Viktorsson, R. Lewensohn, P. Kogner, et al. The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo Mol. Cancer Ther., September 1, 2007; 6(9): 2409 - 2417. [Abstract] [Full Text] [PDF]

				D. Marimpietri, C. Brignole, B. Nico, F. Pastorino, A. Pezzolo, F. Piccardi, M. Cilli, D. Di Paolo, G. Pagnan, L. Longo, et al. Combined Therapeutic Effects of Vinblastine and Rapamycin on Human Neuroblastoma Growth, Apoptosis, and Angiogenesis Clin. Cancer Res., July 1, 2007; 13(13): 3977 - 3988. [Abstract] [Full Text] [PDF]