Cell Membrane is a More Sensitive Target than Cytoplasm to Dense Ionization Produced by Auger Electrons

Abstract

To improve radioimmunotherapy with Auger electron emitters, we assessed whether the biological efficiency of (125)I varied according to its localization. A-431 and SK-OV-3 carcinoma cells were incubated with increasing activities (0-4 MBq/ml) of (125)I-labeled vectors targeting the cell membrane, the cytoplasm or the nucleus. We then measured cell survival by clonogenic assay and the mean radiation dose to the nucleus by assessing the cellular medical internal radiation dose (MIRD). The relationship between survival and the radiation dose delivered was investigated with a linear mixed regression model. For each cell line, we obtained dose-response curves for the three targets and the reference values (i.e., the dose leading to 75, 50 or 37% survival). When cell survival was expressed as a function of the total cumulative decays, nuclear (125)I disintegrations were more harmful than disintegrations in the cytoplasm or at the cell membrane. However, when survival was expressed as a function of the mean radiation dose to the nucleus, toxicity was significantly higher when (125)I was targeted to the cell membrane than to the cytoplasm. These findings indicate that the membrane is a more sensitive target than the cytoplasm for the dense ionization produced by Auger electrons. Moreover, cell membrane targeting is as cytotoxic as nuclear targeting in SK-OV-3 cells. We suggest that targeting the membrane rather than the cytoplasm may contribute to the development of more efficient radioimmunotherapies based on Auger electron radiation, also because most of the available vectors are directed against cell surface antigens.

Monte Carlo Evaluation of Auger Electron–Emitting Theranostic Radionuclides

“…Several strategies have been proposed to optimally localize the radionuclides with respect to the sensitive targets in cells (5,10,11). However, recent observations suggest that nuclear accumulation may not be required in order for an Auger electron-emitter to produce the high-LET type of radiotoxicity (12). In contrast, radionuclides bound outside the cell nucleus (e.g., in the cytoplasm), on the cellular membrane, or extracellularly do not produce severe lethal effects and have a relative biological effectiveness comparable to that observed for low-LET radiation (13).…”

Brief Intraperitoneal Radioimmunotherapy of Small Peritoneal Carcinomatosis Using High Activities of Noninternalizing 125I-Labeled Monoclonal Antibodies

“…One alternative could be the use of short-range particles such as a-emitters (21) or Auger electron emitters. We previously showed that anti-carcinoembryonic antigen (CEA) mAbs labeled with Auger electron emitters and intravenously injected into mice xenografted with cancer cells could significantly delay the growth of small peritoneal solid tumors (7,23). We thus wanted to assess the efficiency and toxicity of 125 I-mAb when used in IP RIT for mice bearing small peritoneal tumors.…”

Emerging Trends for Radioimmunotherapy in Solid Tumors

“…33 The energy of Auger electrons is about 20-50 keV and can travel up to 2-500 nm in tissues. The cytotoxic effects of a-particles and Auger electrons are attributed to their ability to induce DNA damage.…”

“…However, previous in vitro studies from the group demonstrated that in comparison to internalizing radioimmunoconjugates, noninternalizing 125 I-labeled antibodies exhibited more pronounced cell death suggesting the sensitivity of the cell membrane to ionizing radiation. 33 Subsequently, the therapeutic superiority of noninternalizing 125 I-labeled antibodies in treating peritoneal carcinomatosis was demonstrated in vivo using the vulvar squamous carcinoma xenograft model. 20 After intravenous administration, the maximal tumor accretion of 125 I-labeled noninternalizing anti-CEA MAb 35A7 was significantly higher than radioiodinated internalizing anti-EGFR MAb m225.…”