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 GD(2) [aGD(2)-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 aGD(2)-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.