Anti Gd2-Immunoliposome-Mediated Targeting of [¹²⁵I] Metaiodobenzylguanidine to Neuroblastoma and Melanoma Cells in Vitro

Abstract

Patients with neuroblastoma (NB) are often refractory to metabolic radiotherapy with radioiodine-labelled metaiodobenzylguanidine (MIBG), generally due to low, if any, expression of the transporter molecule responsible for MIBG uptake in tumor cells. Delivery of anticancer drugs in sterically stabilized (polyethylene glycol (PEG)-containing) immunoliposomes (SIL) is an emerging tool for the selective delivery of antitumor drugs to cells expressing specific antigens. By taking advantage of receptor-mediated endocytosis of targeted liposomes, the delivery of MIBG to NB cells may be enhanced, bypassing the requirement for a drug-specific membrane transporter. NB cells, as well as some neuroectoderma-derived cell lineages, such as melanoma cells, express frequently disiaioganglioside GD2. This surface disiaioganglioside can, therefore, be utilized as a target to selectively deliver MIBG-loaded SILs to these GD2-expressing cells.

We thus explored the feasibility to encapsulate ¹²⁵I-MIBG into anti-GD2 immunoliposomes and investigated the cellular uptake and metabolism of SIL-MIBG compared to free MIBG in a panel of NB and melanoma cell lines in vitro. We successfully loaded free MIBG into stabilized liposomes and cova-iently coupled them to monoclonal anti-GD2 antibodies.

The relative expression of MIBG-transporter and GD2 determined the degree of MIBG uptake. Uptake of SIL-encapsulated MIBG by all cell lines was higher than that of free MIBG, the only exception being the highly transport-competent, GD2-negative cell line SK-N-BE2c. Moreover, successful incorporation of MIBG in melanoma cells, which are inherently non competent in taking up the free drug, could be achieved by SIL-MIBG. Interestingly, the intracellular half-life of SIL-MIBG was significantly more prolonged than thai of free MIBG in all NB cell lines, which reportedly cannot efficiently store free MIBG in subcellular compartments. The retention of SIL-MIBG by NB and melanoma cells was similar to that observed with free MIBG in highly storage-efficient pheochromocytoma (PC) cells.

Thus, targeting GD2-positive cells with specific MIBG-loaded immunoliposomes appears a novel strategy for tumor cell killing, regardless of their competence to specifically incorporate the free compound.

Keywords::

• Metaiodobenzylguanidine
• Neuroblastoma
• Melanoma
• Immunoliposome
• GD2
• Targeting