title: In vitro and in vivo antitumor activity of liposomal Fenretinide targeted to human neuroblastoma.
abstract: Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. In advanced disease stages, prognosis is poor and treatments have limited efficacy, thus novel strategies are warranted. The synthetic retinoid Fenretinide (HPR) induces apoptosis in NB and melanoma cell lines. We reported an in vitro potentiation of HPR effects on melanoma cells when the drug is incorporated into GD2-targeted immunoliposomes (anti-GD2-SIL-HPR). We investigated the antitumor activity of anti-GD2-SIL-HPR against NB cells, both in vitro and in vivo. Anti-GD2-SIL showed specific, competitive binding to and uptake by, various NB cell lines. In in vitro cytotoxicity studies, NB cells, incubated with 30 microM HPR entrapped in anti-GD2-immunoliposomes, showed a significant reduction in cellular growth compared to free HPR, HPR entrapped in Ab-free liposomes or anti-GD2 empty liposomes. In an in vivo NB metastatic model, we demonstrated that anti-GD2-SIL-HPR completely inhibited the development of macroscopic and microscopic metastases in comparison to controls. Similar, but significantly less potent, antitumor effect was observed also in mice treated with anti-GD2 immunoliposomes without HPR (anti-GD2-SIL-blank) or anti-GD2 MAb alone (p = 0.0297 and p = 0.0294, respectively, vs. anti-GD2-SIL-HPR). Moreover, our results clearly demonstrated that although anti-GD2 MAb had a strong antitumor effect in this in vivo NB model, 100% curability was obtained only after treatment with anti-GD2-SIL-HPR (p < 0.0001). Anti-GD2 liposomal HPR should receive clinical evaluation as adjuvant therapy of neuroblastoma.
authors.affiliation: Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pagnan
authors.forename: Fabio
authors.initials: F
authors.lastname: Pastorino
authors.forename: Emilio
authors.initials: E
authors.lastname: Cosimo
authors.forename: Chiara
authors.initials: C
authors.lastname: Brignole
authors.forename: Danilo
authors.initials: D
authors.lastname: Marimpietri
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Montaldo
authors.forename: Claudia
authors.initials: C
authors.lastname: Gambini
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Allen
authors.forename: Emil
authors.initials: E
authors.lastname: Bogenmann
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division; D004195:Disease Models, Animal; D017313:Fenretinide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology*; D016019:Survival Analysis; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D008081:Liposomes; D017313:Fenretinide