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 nonspecific 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 M 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.

Mechanisms of fenretinide-induced apoptosis

“…D . R A R s [ 76] Glioma [213,214] N.D. N.D. Head and Neck Carcinoma [71,77,162,215] Intrinsic [162] R O S [ 71,77,162], RARs [71,77], and JNK [162] Hepatoma [113,159,195] Intrinsic [113,159,195] R O S [ 113,159], Caspase-8 [195] Leukemia [20,21,26,27,93,98,105,107,132,134,196] Intrinsic [138,219,220] N.D.…”

Targeting Therapeutic and Imaging Agents to Folate Receptor Positive Tumors

“…Thus, cell-specific targeting ligands (e.g. FA) have often been added to many liposome formulations with the intent of improving the cellular uptake and deposition of drug-encapsulated liposomes [62][63][64].…”

Antitumor Effect of Paclitaxel-Loaded PEGylated Immunoliposomes Against Human Breast Cancer Cells

“…Immunoliposomes are liposomes designed to actively target solid tumors by virtue of the monoclonal or polyclonal antibodies attached to their surface (18)(19)(20). Immunoliposomes have the potential to transfer large numbers of drug molecules to tumor cells, and drugs delivered via immunoliposomes have antitumor activities similar to or greater than those of the drug alone (21).…”