In vitro and in vivo antitumor activity of liposomal Fenretinide targeted to human neuroblastoma

Lizzia Raffaghello, Gabriella Pagnan, Fabio Pastorino, Emilio Cosimo, Chiara Brignole, Danilo Marimpietri, Paolo G. Montaldo, Claudia Gambini, Theresa M. Allen, Emil Bogenmann, Mirco Ponzoni

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 μM 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.

Original languageEnglish
Pages (from-to)559-567
Number of pages9
JournalInternational Journal of Cancer
Volume104
Issue number5
DOIs
Publication statusPublished - May 1 2003

Fingerprint

Fenretinide
Neuroblastoma
Liposomes
Melanoma
Cell Line
Competitive Binding
In Vitro Techniques
Retinoids
Therapeutics
Apoptosis
Neoplasm Metastasis

Keywords

  • Disialoganglioside 2
  • Fenretinide
  • Immunoliposomes
  • Neuroectodermal tumors
  • Targeted drug delivery

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

In vitro and in vivo antitumor activity of liposomal Fenretinide targeted to human neuroblastoma. / Raffaghello, Lizzia; Pagnan, Gabriella; Pastorino, Fabio; Cosimo, Emilio; Brignole, Chiara; Marimpietri, Danilo; Montaldo, Paolo G.; Gambini, Claudia; Allen, Theresa M.; Bogenmann, Emil; Ponzoni, Mirco.

In: International Journal of Cancer, Vol. 104, No. 5, 01.05.2003, p. 559-567.

Research output: Contribution to journalArticle

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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 μM 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.",
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AU - Raffaghello, Lizzia

AU - Pagnan, Gabriella

AU - Pastorino, Fabio

AU - Cosimo, Emilio

AU - Brignole, Chiara

AU - Marimpietri, Danilo

AU - Montaldo, Paolo G.

AU - Gambini, Claudia

AU - Allen, Theresa M.

AU - Bogenmann, Emil

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AB - 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 μM 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.

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