During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRT) are based on a multidisciplinary approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT) and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure and low absorbed dose rate) differ from those of conventional EBRT (homogeneous irradiation, short exposure and high absorbed dose rate), and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose-effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related) and non-targeted effects (assumed to be non-dose-related) of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main challenges of TRT.

Aims: We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with ¹²⁵ I [ ¹²⁵ I-mAbs]). Results: We showed that the cytotoxicity of ¹²⁵ I-mAbs targeting the cell membrane of p53 ^+/+ HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. ¹²⁵ I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca ²⁺ fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2′-deoxyuridine to the nucleus was comparable to that of ¹²⁵ I-mAb against cell surface receptors. In vivo , we found that the statistical significance of tumor growth delay induced by ¹²⁵ I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also. Innovation: Low-energy Auger electrons, such as those emitted by ¹²⁵ I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with ¹²⁵ I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting. Conclusion: Our findings describe the mechanisms involved in the efficacy of ¹²⁵ I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal . 25, 467–484.

Radioimmunotherapy (RIT) represents an attractive tool for the treatment of local and/or diffuse tumors with radiation. In RIT, cytotoxic radionuclides are delivered by monoclonal antibodies that specifically target tumor-associated antigens or the tumor microenvironment. While RIT has been successfully employed for the treatment of lymphoma, mostly with radiolabeled antibodies against CD20 (Bexxar(®); Corixa Corp., WA, USA and Zevalin(®); Biogen Idec Inc., CA, USA and Schering AG, Berlin, Germany), its use in solid tumors is more challenging and, so far, few trials have progressed beyond Phase II. This review provides an update on antibody-radionuclide conjugates and their use in RIT. It also discusses possible optimization strategies to improve the clinical response by considering biological, radiobiological and physical features.

Purpose: For the development of new anti-cancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of non-targeted effects in non-irradiated neighboring cells because they may affect the therapeutic efficacy and contribute to side effects. Experimental Design: Here, we investigated the contribution of non-targeted cytotoxic and genotoxic effects in vitro and in vivo in (xenografted mice) during alpha (²¹²Pb/²¹²Bi, ²¹³Bi) and Auger (¹²⁵I) radioimmunotherapy (RIT). Results: Between 67 and 94% (alpha RIT) and 8 and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7-36% (alpha RIT) and 27-29% (Auger RIT) of cells were killed by non-targeted effects. We then demonstrated that the non-targeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and c-JUN N-terminal kinases (JNK). Reactive oxygen species also played a significant role in these non-targeted effects, as demonstrated by NF-kB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival in vitro and to larger tumors and less tissue DNA damage in vivo. These results were supported by an inhibitory effect of pravastatin on Auger RIT. Conclusions: Cell membrane-mediated non-targeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.

Background: The use of mesenchymal stem cells (MSCs) appears to be a promising therapeutic approach for cardiac repair after myocardial infarction. However, clinical trials have revealed the need to improve their therapeutic efficacy. Recent evidence demonstrated that mitochondria undergo spontaneous transfer from damaged cells to MSCs, resulting in the activation of the cytoprotective and pro-angiogenic functions of recipient MSCs. Based on these observations, we investigated whether the preconditioning of MSCs with mitochondria could optimize their therapeutic potential for ischemic heart disease. Methods: Human MSCs were exposed to mitochondria isolated from human fetal cardiomyocytes. After 24 h, the effects of mitochondria preconditioning on the MSCs’ function were analyzed both in vitro and in vivo. Results: We found that cardiac mitochondria-preconditioning improved the proliferation and repair properties of MSCs in vitro. Mechanistically, cardiac mitochondria mediate their stimulatory effects through the production of reactive oxygen species, which trigger their own degradation in recipient MSCs. These effects were further confirmed in vivo, as the mitochondria preconditioning of MSCs potentiated their therapeutic efficacy on cardiac function following their engraftment into infarcted mouse hearts. Conclusions: The preconditioning of MSCs with the artificial transfer of cardiac mitochondria appears to be promising strategy to improve the efficacy of MSC-based cell therapy in ischemic heart disease.