Targeting liposomal chemotherapy via both tumor cell-specific and tumor vasculature-specific ligands potentiates therapeutic efficacy.
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.
Pastorino
Fabio
F
Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
Brignole
Chiara
C
Di Paolo
Daniela
D
Nico
Bice
B
Pezzolo
Annalisa
A
Marimpietri
Danilo
D
Pagnan
Gabriella
G
Piccardi
Federica
F
Cilli
Michele
M
Longhi
Renato
R
Ribatti
Domenico
D
Corti
Angelo
A
Allen
Theresa M
TM
Ponzoni
Mirco
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D058851:GPI-Linked Proteins; D005732:Gangliosides / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009185:Myelin Proteins / Q000008:administration & dosage / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D009447:Neuroblastoma / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D000070816:Nogo Receptor 1; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000008:administration & dosage / Q000378:metabolism*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D058851:GPI-Linked Proteins; D005732:Gangliosides; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; D010446:Peptide Fragments; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface; C019403:ganglioside, GD2; D004317:Doxorubicin