Immunoliposomal fenretinide: a novel antitumoral drug for human neuroblastoma.
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). Here, we investigated the antitumor activity of anti-GD2-SIL-HPR against NB cells, both in vitro and in vivo. Anti-GD2-immunoliposomes (anti-GD2-SIL) showed specific, competitive binding to, and uptake by, various NB cell lines. Moreover, anti-GD2-SIL-HPR presented increased selectivity and efficacy in inhibiting NB cell proliferation through the induction of apoptosis, compared to free drug and SL-HPR. 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. However, 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 following treatment with anti-GD2-SIL-HPR (P<0.0001). Anti-GD2 liposomal HPR should receive clinical evaluation as adjuvant therapy of neuroblastoma.
Raffaghello
L
L
Laboratory of Oncology, G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16148 Genoa, Italy. lizziaraffaghello@ospedale-gaslini.ge.it
Pagnan
G
G
Pastorino
F
F
Cosimo
E
E
Brignole
C
C
Marimpietri
D
D
Bogenmann
E
E
Ponzoni
M
M
Montaldo
P G
PG
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division; D004195:Disease Models, Animal; D017313:Fenretinide / Q000008:administration & dosage*; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D008081:Liposomes; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005732:Gangliosides; D008081:Liposomes; C025447:sialogangliosides; D017313:Fenretinide