title: Enhanced anti-tumor and anti-angiogenic efficacy of a novel liposomal fenretinide on human neuroblastoma.
abstract: Neuroblastoma is an embryonal tumor originating from the simpatico-adrenal lineage of the neural crest. It approximately accounts for about 15% of all pediatric oncology deaths. Despite advances in multimodal therapy, metastatic neuroblastoma tumors at diagnosis remain a clinical challenge. Retinoids are a class of compounds known to induce both terminal differentiation and apoptosis/necrosis of neuroblastoma cells. Among them, fenretinide (HPR) has been considered one of the most promising anti-tumor agent but it is partially efficacious due to both poor aqueous solubility and rapid metabolism. Here, we have developed a novel HPR formulation, by which the drug was encapsulated into sterically stabilized nanoliposomes (NL[HPR]) according to the Reverse Phase Evaporation method. This procedure led to a higher structural integrity of liposomes in organic fluids for a longer period of time, in comparison with our previous liposomal formulation developed by the film method. Moreover, NL[HPR] were further coupled with NGR peptides for targeting the tumor endothelial cell marker, aminopeptidase N (NGR-NL[HPR]). Orthotopically xenografted neuroblastoma-bearing mice treated with NGR-NL[HPR] lived statistically longer than mice untreated or treated with free HPR (NGR-NL[HPR] vs both control and HPR: P<0.0001). Also, NL[HPR] resulted in a statistically improved survival (NL[HPR] vs both control and HPR: P<0.001) but to a less extent if compared with that obtained with NGR-NL[HPR] (NGR-NL[HPR] vs NL[HPR]: P<0.01). Staining of tumor sections with antibodies specific for neuroblastoma and for either pericytes or endothelial cells evidenced that HPR reduced neuroblastoma growth through both anti-tumor and anti-angiogenic effects, mainly when delivered by NGR-NL[HPR]. Indeed, in this group of mice a marked reduction of tumor progression, of intra-tumoral vessel counts and VEGF expression, together with a marked down-modulation of matrix metalloproteinases MMP2 and MMP9, was observed. In conclusion, the use of this novel targeted delivery system for the apoptotic and antiangiogenic drug, fenretinide, could be considered as an adjuvant tool in the future treatment of neuroblastoma patients.
authors.affiliation: Experimental Therapies Unit, Laboratory of Oncology, Istituto Giannina Gaslini, 16148 Genoa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Paolo
authors.forename: Fabio
authors.initials: F
authors.lastname: Pastorino
authors.forename: Guendalina
authors.initials: G
authors.lastname: Zuccari
authors.forename: Irene
authors.initials: I
authors.lastname: Caffa
authors.forename: Monica
authors.initials: M
authors.lastname: Loi
authors.forename: Danilo
authors.initials: D
authors.lastname: Marimpietri
authors.forename: Chiara
authors.initials: C
authors.lastname: Brignole
authors.forename: Patrizia
authors.initials: P
authors.lastname: Perri
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pagnan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D017313:Fenretinide
keywords: Fenretinide; Nanoliposomes; Neuroblastoma; Targeted therapy; Vascular targeting