Intracellular localization of metaiodobenzyl guanidine in human neuroblastoma cells by electron spectroscopic imaging

Abstract

The targeted radiotherapy of neuroblastoma with 131l-labelled metaiodobenzyl guanidine (mIBG) is now the subject of several clinical studies. The precise intracellular localization of mIBG, necessary for nuclear microdosimetry, has not previously been described. We report the use of electron-energy-loss spectroscopy and electron spectroscopic imaging to establish the intracellular distribution of mIBG in cells from the human neuroblastoma line NBI-G which had been incubated with the drug by mapping iodine in ultra-thin sections of tumours. Most of the iodine is found within the mitochondria, with lesser amounts in the vesicles and on the nuclear membrane. The use of alternative radionuclides with different physical characteristics has been suggested to optimize the efficacy of this therapeutic strategy. The lack of penetration of mIBG into the nucleoplasm means that ultra-short-range Auger electron emitters such as 125I are not likely to prove more cytotoxic than 131I.

Radionuclide targeting and dosimetry at the microscopic level: the role of microautoradiography

“…Perhaps because of the use of conventional chemical fixation and embedding methods, this result disagrees with the finding by other methods that the drug is absent from nuclei [29,77]. This predicts that therapy of neuroblastoma with 125I-rather than 131I-labelled MIBG is unlikely to be successful.…”

Radioiodinated metaiodobenzylguanidine: a review of its biodistribution and pharmacokinetics, drug interactions, cytotoxicity and dosimetry

“…Conversely, the mitochondria [33] and even the nucleus [34] have been reported to contain radioactivity after incubation with radioiodinated MIBG. However, these results should be interpreted with caution, as the conventional fixation procedures used for analysis could not prevent diffusion of the drug from its original site during preparation [30].…”

m‐Iodobenzylguanidine increases the mitochondrial Ca2+ pool in isolated hepatocytes

“…However, the ira. munosuppressant has been shown to inhibit the prooxidant-induced pyridine nucleotide hydrolysis [9,10] and is therefore believed to act prior to the step regulated by MIBG is actively accumulated by cells and is predominantly concentrated in the mitochondria [26]. MIBG can also function as a complex I inhibitor of the mitochondrial respiratory chain and thi~ is probably the mechanism which accounts for the cytotoxicity observed with high concentrations of the inhibitor [21].…”