Enhanced anti-tumor and anti-angiogenic efficacy of a novel liposomal fenretinide on human neuroblastoma

Daniela Di Paolo, Fabio Pastorino, Guendalina Zuccari, Irene Caffa, Monica Loi, Danilo Marimpietri, Chiara Brignole, Patrizia Perri, Michele Cilli, Beatrice Nico, Domenico Ribatti, Vito Pistoia, Mirco Ponzoni, Gabriella Pagnan

Research output: Contribution to journalArticlepeer-review

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, ami-nopeptidase 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 b 0.0001). Also, NL[HPR] resulted in a statistically improved survival (NL[HPR] vs both control and HPR: P b 0.001) but to a less extent if compared with that obtained with NGR-NL[HPR] (NGR-NL[HPR] vs NL[HPR]: P b 0.01). Staining of tumor sections with antibodies specific for neuroblastoma and for either pericytes or endo-thelial 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.

Original languageEnglish
Pages (from-to)445-451
Number of pages7
JournalJournal of Controlled Release
Volume170
Issue number3
DOIs
Publication statusPublished - 2013

Keywords

  • Fenretinide
  • Nanoliposomes
  • Neuroblastoma
  • Targeted therapy
  • Vascular targeting

ASJC Scopus subject areas

  • Pharmaceutical Science

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