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GD2-mediated melanoma cell targeting and cytotoxicity of liposome-entrapped fenretinide.

Abstract：

:Melanoma is a highly malignant and increasingly common neoplasm. Because metastatic melanoma remains incurable, new treatment approaches are needed. Immunoliposomes have been previously shown to enhance the selective localization of immunoliposome-entrapped drugs to solid tumors with improvements in the therapeutic index of the drugs. Previously, we reported that the synthetic retinoid fenretinide (HPR) is an inducer of apoptosis in neuroblastoma (NB) cells, sharing the neuroectodermal origin with melanoma cells. HPR is a strong inducer of apoptosis also in melanoma cells, although at doses 10-fold higher than those achievable clinically. Thus, our purpose was to investigate the in vitro potentiation of its cytotoxic effect on melanoma cells in combination with long-circulating GD2-targeted immunoliposomes. GD2 is a disialoganglioside extensively expressed on tumors of neuroectodermal origin, including melanoma. Murine anti-GD2 antibody (Ab) 14.G2a and its human/mouse chimeric variant ch14.18 have been ligated to sterically stabilized liposomes by covalent coupling of Ab to the polyethylene glycol (PEG) terminus. Ab-bearing liposomes showed specific, competitive binding to and uptake by various melanoma cell lines compared with liposomes bearing non-specific isotype-matched Abs or Ab-free liposomes. Cytotoxicity was evaluated after 2 hr treatment, followed by extensive washing and 72 hr incubation. This treatment protocol was designed to minimize non-specific adsorption of liposomes to the cells, while allowing for maximum Ab-mediated binding. When melanoma cells were incubated with 30 microM HPR entrapped in anti-GD2 liposomes, a significant reduction in cellular growth was observed compared to free HPR, entrapped HPR in Ab-free liposomes or empty liposomes. Cytotoxicity was not evident in tumor cell lines of other origins that did not express GD2. Growth of NB cells was also inhibited by immunoliposomes with entrapped HPR.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Pagnan G,Montaldo PG,Pastorino F,Raffaghello L,Kirchmeier M,Allen TM,Ponzoni M

doi

10.1002/(sici)1097-0215(19990412)81:2<268::aid-ijc

keywords:

subject

Has Abstract

pub_date

1999-04-12 00:00:00

pages

268-74

issue

eissn

0020-7136

issn

1097-0215

pii

10.1002/(SICI)1097-0215(19990412)81:2<268::AID-IJC

journal_volume

pub_type

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GD2-mediated melanoma cell targeting and cytotoxicity of liposome-entrapped fenretinide.