Doxorubicin-loaded Fab′ fragments of anti-disialoganglioside immunoliposomes selectively inhibit the growth and dissemination of human neuroblastoma in nude mice

Fabio Pastorino, Chiara Brignole, Danilo Marimpietri, Puja Sapra, Elaine H. Moase, Theresa M. Allen, Mirco Ponzoni

Research output: Contribution to journalArticle

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Intensive therapeutic intervention does not prolong the overall disease-free survival rate for this tumor. NB tumor, but not normal tissues, overexpress the disialoganglioside (GD2) at the cell surface. Anti-GD2 whole antibodies (aGD2) or their corresponding Fab′ fragments were covalently coupled to Stealth immunoliposomes (aGD2-SIL or Fab′-SIL), and their binding to GD2-positive NB cells was measured. Cytotoxic effects of immunoliposomes loaded with doxorubicin (DXR) were determined. Radiolabelled immunoliposomes were used to evaluate pharmacokinetics (PK). The effectiveness of different liposomal formulations of DXR was tested against a metastatic model of human NB in nude mice. aGD2-SIL and Fab′-SIL showed concentration-dependent specific binding and uptake by GD2-positive NB cells. DXR entrapped in aGD2-SIL or Fab′-SIL (aGD2-SIL[DXR], Fab′-SIL[DXR]) showed higher cytotoxicities than nontargeted liposomes (SL[DXR]). DXR-loaded Fab′-SIL (Fab′-SIL[DXR]) also showed specific binding, uptake, and cytotoxic effects on several GD2-positive NB cells in vitro. PK studies showed that Fab′-SIL had long-circulating profiles in blood compared with aGD2-SIL, with the PK profile for Fab′-SIL being almost identical to that obtained with nontargeted Stealth liposomes. In vivo, long-term survivors were obtained in mice treated with Fab′-SIL[DXR] but not in untreated animals, or those treated with free aGD2 Fab′, Fab′-SIL (no drug), free-DXR, or nontargeted Stealth liposomes (no antibody; P <0.0001). Immunoliposomes containing DXR prevented the establishment and growth of the tumor in all of the organs examined. In conclusion, Fab′-SIL[DXR] formulations led to the total inhibition of metastatic growth of human NB in a nude mouse metastatic model. This formulation should receive clinical evaluation as adjuvant therapy of NB.

Original languageEnglish
Pages (from-to)86-92
Number of pages7
JournalCancer Research
Volume63
Issue number1
Publication statusPublished - Jan 1 2003

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Immunoglobulin Fab Fragments
Neuroblastoma
Nude Mice
Doxorubicin
Growth
Liposomes
Pharmacokinetics
Neoplasms
sialogangliosides
Antibodies
Disease-Free Survival
Survivors
Survival Rate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{f6f4cafa7ca8423db0ab0bf0c0ae7ebb,
title = "Doxorubicin-loaded Fab′ fragments of anti-disialoganglioside immunoliposomes selectively inhibit the growth and dissemination of human neuroblastoma in nude mice",
abstract = "Neuroblastoma (NB) is the most common extracranial solid tumor in children. Intensive therapeutic intervention does not prolong the overall disease-free survival rate for this tumor. NB tumor, but not normal tissues, overexpress the disialoganglioside (GD2) at the cell surface. Anti-GD2 whole antibodies (aGD2) or their corresponding Fab′ fragments were covalently coupled to Stealth immunoliposomes (aGD2-SIL or Fab′-SIL), and their binding to GD2-positive NB cells was measured. Cytotoxic effects of immunoliposomes loaded with doxorubicin (DXR) were determined. Radiolabelled immunoliposomes were used to evaluate pharmacokinetics (PK). The effectiveness of different liposomal formulations of DXR was tested against a metastatic model of human NB in nude mice. aGD2-SIL and Fab′-SIL showed concentration-dependent specific binding and uptake by GD2-positive NB cells. DXR entrapped in aGD2-SIL or Fab′-SIL (aGD2-SIL[DXR], Fab′-SIL[DXR]) showed higher cytotoxicities than nontargeted liposomes (SL[DXR]). DXR-loaded Fab′-SIL (Fab′-SIL[DXR]) also showed specific binding, uptake, and cytotoxic effects on several GD2-positive NB cells in vitro. PK studies showed that Fab′-SIL had long-circulating profiles in blood compared with aGD2-SIL, with the PK profile for Fab′-SIL being almost identical to that obtained with nontargeted Stealth liposomes. In vivo, long-term survivors were obtained in mice treated with Fab′-SIL[DXR] but not in untreated animals, or those treated with free aGD2 Fab′, Fab′-SIL (no drug), free-DXR, or nontargeted Stealth liposomes (no antibody; P <0.0001). Immunoliposomes containing DXR prevented the establishment and growth of the tumor in all of the organs examined. In conclusion, Fab′-SIL[DXR] formulations led to the total inhibition of metastatic growth of human NB in a nude mouse metastatic model. This formulation should receive clinical evaluation as adjuvant therapy of NB.",
author = "Fabio Pastorino and Chiara Brignole and Danilo Marimpietri and Puja Sapra and Moase, {Elaine H.} and Allen, {Theresa M.} and Mirco Ponzoni",
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pages = "86--92",
journal = "Journal of Cancer Research",
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T1 - Doxorubicin-loaded Fab′ fragments of anti-disialoganglioside immunoliposomes selectively inhibit the growth and dissemination of human neuroblastoma in nude mice

AU - Pastorino, Fabio

AU - Brignole, Chiara

AU - Marimpietri, Danilo

AU - Sapra, Puja

AU - Moase, Elaine H.

AU - Allen, Theresa M.

AU - Ponzoni, Mirco

PY - 2003/1/1

Y1 - 2003/1/1

N2 - Neuroblastoma (NB) is the most common extracranial solid tumor in children. Intensive therapeutic intervention does not prolong the overall disease-free survival rate for this tumor. NB tumor, but not normal tissues, overexpress the disialoganglioside (GD2) at the cell surface. Anti-GD2 whole antibodies (aGD2) or their corresponding Fab′ fragments were covalently coupled to Stealth immunoliposomes (aGD2-SIL or Fab′-SIL), and their binding to GD2-positive NB cells was measured. Cytotoxic effects of immunoliposomes loaded with doxorubicin (DXR) were determined. Radiolabelled immunoliposomes were used to evaluate pharmacokinetics (PK). The effectiveness of different liposomal formulations of DXR was tested against a metastatic model of human NB in nude mice. aGD2-SIL and Fab′-SIL showed concentration-dependent specific binding and uptake by GD2-positive NB cells. DXR entrapped in aGD2-SIL or Fab′-SIL (aGD2-SIL[DXR], Fab′-SIL[DXR]) showed higher cytotoxicities than nontargeted liposomes (SL[DXR]). DXR-loaded Fab′-SIL (Fab′-SIL[DXR]) also showed specific binding, uptake, and cytotoxic effects on several GD2-positive NB cells in vitro. PK studies showed that Fab′-SIL had long-circulating profiles in blood compared with aGD2-SIL, with the PK profile for Fab′-SIL being almost identical to that obtained with nontargeted Stealth liposomes. In vivo, long-term survivors were obtained in mice treated with Fab′-SIL[DXR] but not in untreated animals, or those treated with free aGD2 Fab′, Fab′-SIL (no drug), free-DXR, or nontargeted Stealth liposomes (no antibody; P <0.0001). Immunoliposomes containing DXR prevented the establishment and growth of the tumor in all of the organs examined. In conclusion, Fab′-SIL[DXR] formulations led to the total inhibition of metastatic growth of human NB in a nude mouse metastatic model. This formulation should receive clinical evaluation as adjuvant therapy of NB.

AB - Neuroblastoma (NB) is the most common extracranial solid tumor in children. Intensive therapeutic intervention does not prolong the overall disease-free survival rate for this tumor. NB tumor, but not normal tissues, overexpress the disialoganglioside (GD2) at the cell surface. Anti-GD2 whole antibodies (aGD2) or their corresponding Fab′ fragments were covalently coupled to Stealth immunoliposomes (aGD2-SIL or Fab′-SIL), and their binding to GD2-positive NB cells was measured. Cytotoxic effects of immunoliposomes loaded with doxorubicin (DXR) were determined. Radiolabelled immunoliposomes were used to evaluate pharmacokinetics (PK). The effectiveness of different liposomal formulations of DXR was tested against a metastatic model of human NB in nude mice. aGD2-SIL and Fab′-SIL showed concentration-dependent specific binding and uptake by GD2-positive NB cells. DXR entrapped in aGD2-SIL or Fab′-SIL (aGD2-SIL[DXR], Fab′-SIL[DXR]) showed higher cytotoxicities than nontargeted liposomes (SL[DXR]). DXR-loaded Fab′-SIL (Fab′-SIL[DXR]) also showed specific binding, uptake, and cytotoxic effects on several GD2-positive NB cells in vitro. PK studies showed that Fab′-SIL had long-circulating profiles in blood compared with aGD2-SIL, with the PK profile for Fab′-SIL being almost identical to that obtained with nontargeted Stealth liposomes. In vivo, long-term survivors were obtained in mice treated with Fab′-SIL[DXR] but not in untreated animals, or those treated with free aGD2 Fab′, Fab′-SIL (no drug), free-DXR, or nontargeted Stealth liposomes (no antibody; P <0.0001). Immunoliposomes containing DXR prevented the establishment and growth of the tumor in all of the organs examined. In conclusion, Fab′-SIL[DXR] formulations led to the total inhibition of metastatic growth of human NB in a nude mouse metastatic model. This formulation should receive clinical evaluation as adjuvant therapy of NB.

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