ИСТИНА

Auger electron (AE) emitters possess extremely enhanced cytotoxicity when decaying in close proximity to nuclear DNA. Thus, when precisely delivered to the nuclei of cancer cells, they might be ideal for killing single tumor cells with minimal non-specific damage to normal tissues. Modular nanotransporters (MNTs), designed to transport drugs from the cell surface via receptor-mediated endocytosis and subsequent endosomal escape to the nucleus, are a potential platform for accomplishing this goal. We evaluated the potential utility of MNT for enhancing the nuclear delivery and cytotoxicity of two different AE emitters – the prototypical AE, 125I, and 67Ga, which possesses a nearly ideal half-life for ultimate clinical application for cancer therapy. In this study we chose an MNT with epidermal growth factor (EGF) as the targeting ligand because EGF receptors are overexpressed on a great variety of cancer cells. For radioiodination we utilized the residualizing labeling reagent N-succinimidyl 4- guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB), that yields labeled proteins that do not undergo appreciable deiodination in vivo. For labeling MNT with 67Ga, we selected 2,2!,2!!-(1,4,7-triazonane- 1,4,7-triyl)triacetic acid (NOTA), which forms highly stable complexes with Ga(III). MNT was labeled efficiently with both AE emitting isotopes. Both radiolabeled derivatives internalized effectively into EGFRoverexpressing cells, with more than half (55–60%) located within the cell nuclei after 1 h incubation. The cytotoxicity of both [125I]SGMIB-MNT and 67Ga-NOTA-MNT compared to labeled bovine serum albumin control was enhanced up to a factor of more than 3700 depending on the isotope, the cell line and its EGFR expression level. Moreover, both radiolabeled derivatives also showed 18-fold enhanced cytotoxic effectiveness over [125I]SGMIB-EGF or 67Ga-NOTA-EGF. Taken together, our results demonstrate that MNT is a promising platform for targeted radiotherapy utilizing AE emitting radionuclides, and we speculate that this approach will be most valuable in situations where the tumor specificity of the effect is most critical.