Biodistribution et toxicité des nanocapsules chargées en 188Re après injection intratumorale par convection enhanced delivery chez la souris

Objectifs Déterminer la faisabilité, l’intérêt et la toxicité hématologique de l’administration intratumorale par convection enhanced delivery (CED) de nanocapsules chargées en 188Re (NCL-188Re). Matériels et méthodes L’étude de biodistribution des NCL-188Re vs perrhénate (188ReO4−) a été réalisée sur des souris nude (n = 30). Les animaux ont été séparés en 2 groupes : injection intratumorale de 188ReO4− pour le premier groupe (n = 15, 3 MBq) et de NCL-188Re pour le second groupe (n = 15, 3 MBq). Les animaux ont été sacrifiés à 1 h (n = 10), 24 h (n = 10) et 72 h (n = 10) après l’injection, les organes prélevés et comptés. La toxicité hématologique des NCL-188Re a été évaluée par prises de sang de 50 μL (sinus rétro-orbitaire) réalisées à j2, j7, j14 et j21 après traitement par NaCl (n = 4), NCL-188Re (3 MBq, n = 4), NCL-188Re (6 MBq, n = 4) et NCL-188Re (12 MBq, n = 4). Résultats La vectorisation par NCL a permis de limiter l’élimination urinaire du 188Re puisque dès 24 h post-IV 0,1 ± 0,1 % de la dose injectée (%D.I.) vs 81,9 ± 7,5 % D.I. sont retrouvés dans les urines pour les formes NCL188Re-SSS et 188ReO4-, respectivement, (p = 0,016). Celle-ci permet également de retrouver une activité significativement supérieure dans la tumeur à tous les temps de l’étude. L’administration unique de NCL-188Re a induit une toxicité modérée pour les activités injectées les plus élevées (12 MBq) se manifestant principalement par une thrombopénie transitoire de nadir j14–j18. Il n’a pas été observé de toxicité au niveau des autres lignées cellulaires pour les activités administrées de 3 et 6 MBq. Conclusions Les résultats obtenus montrent la faisabilité de l’injection intratumorale par CED et l’intérêt de la vectorisation du 188Re par les NCL. Les premiers signes de toxicité hématologiques sont en faveur du fractionnement des doses administrées et d’un meilleur ciblage par fonctionnalisation des NCL aux oestrogènes pour permettre une meilleure rétention tumorale

Cowries in the archaeology of West Africa: the present picture

Despite the perceived importance of cowrie shells as indicators of long-distance connections in the West African past, their distribution and consumption patterns in archaeological contexts remain surprisingly underexplored, a gap that is only partly explicable by the sparse distribution of archaeological sites within the sub-continent. General writings on the timeline of importation of cowries into West Africa often fail to take into account the latest archaeological evidence and rely instead on accounts drawn from historical or ethnographic documents. This paper is based on a first-hand assessment of over 4500 shells from 78 sites across West Africa, examining chronology, shell species and processes of modification to assess what distribution patterns can tell us about the history of importation and usage of cowries. These first-hand analyses are paralleled by a consideration of published materials. We re-examine the default assumption that two distinct routes of entry existed — one overland from North Africa before the fifteenth century, another coming into use from the time sea links were established with the East African coast and becoming predominant by the middle of the nineteenth century. We focus on the eastern part of West Africa, where the importance of imported cowries to local communities in relatively recent periods is well known and from where we have a good archaeological sample. The conclusion is that on suitably large assemblages shell size can be an indication of provenance and that, while the present archaeological picture seems largely to confirm historical sources, much of this may be due to the discrepancy in archaeological data available from the Sahara/Sahel zone compared to the more forested regions of the sub-continent. Future archaeological work will clarify this matter

On the typology and the worship status of sacred trees with a special reference to the Middle East

This article contains the reasons for the establishment of sacred trees in Israel based on a field study. It includes 97 interviews with Muslim and Druze informants. While Muslims (Arabs and Bedouins) consider sacred trees especially as an abode of righteous figures' (Wellis') souls or as having a connection to their graves, the Druze relate sacred trees especially to the events or deeds in the lives of prophets and religious leaders. A literary review shows the existence of 24 known reasons for the establishment of sacred trees worldwide, 11 of which are known in Israel one of these is reported here for the first time. We found different trends in monotheistic and polytheistic religions concerning their current worship of sacred trees

p53 Status and Tumor Cell Response to Radioimmunotherapy using 125I-mAbs

Introduction: While radioimmunotherapy (RIT) of non-Hodgkins B-cell lymphoma with Zevalin® and Bexxar ® (anti-CD20 labelled to 90Y or 131I) has demonstrated its efficiency. However, new strategies must be developed in order to treat solid tumours by RIT. In a previous study, we proposed to use the highly cytotoxic Auger electrons emitted by 125I to overcome the radioresistance of solid tumours. We showed that tumour killing achieved with non-internalizing labeled monoclonal antibodies (mAbs) is more significant than that of internalizing 125I-mAbs. This suggests that while the nucleus remains the main target of irradiation, the membrane is also a sensitive target. In the present study, we investigated the role of the nuclear p53 protein and that of ceramide, a major mediator of apoptosis, in the cellular response to 125I mAbs exposure. Material and Methods: Two carcinoma colic cell lines, H3E5 (p53 wt) and HCT116-KO (p53 deficient) expressing cell surface HER1 and CEA receptors were exposed for 2 days to increasing activities (04 MBq/mL) of either internalizing (anti-HER1) or non-internalizing (anti-CEA) 125I-mAbs. Survival was assessed by standard clonogenic assay and dosimetry was investigated using the MIRD scheme. For this purpose, uptake of radioactivity per cell was measured, and S-factors for 125I were specifically calculated for cell surface and cell cytoplasm localisation. Then, first experiments were carried out with alkaline comet assay to observe DNA damage from RIT. Results: For both cell lines, we confirmed that the toxicity due to 125I decays was greater with non-internalizing rather than with internalizing 125I-mAbs. Moreover, we showed that H3E5 cell line was more sensitive to X-ray external beam irradiation rather than HCT116-KO. By contrast, for both 125I localisations, preliminary experiment showed no significant difference on the survival between the two cell lines. These results would indicate that p53 status does not mediate the response to RIT with Auger electrons. A tentative explanation may involve the low dose rate induced by RIT. Under these conditions, no detectable DNA damage was measured by the alkaline comet assay. Conclusion: Our preliminary results seem to indicate that p53 status does not interfere with tumour cell response to RIT. Ongoing experiments are assessing the role of ceramide as a mediator of apoptosis, to explain membrane irradiation efficiency

From bench to bedside: 64Cu/177Lu 1C1m-Fc anti TEM-1: mice-to-human dosimetry extrapolations for future theranostic applications.

The development of diagnostic and therapeutic radiopharmaceuticals is an hot topic in nuclear medicine. Several radiolabeled antibodies are under development necessitating both biokinetic and dosimetry extrapolations for effective human translation. The validation of different animal-to-human dosimetry extrapolation methods still is an open issue. This study reports the mice-to-human dosimetry extrapolation of <sup>64</sup> Cu/ <sup>177</sup> Lu 1C1m-Fc anti-TEM-1 for theranostic application in soft-tissue sarcomas. We adopt four methods; direct mice-to-human extrapolation (M1); dosimetry extrapolation considering a relative mass scaling factor (M2), application of a metabolic scaling factor (M3) and combination of M2 and M3 (M4). Predicted in-human dosimetry for the [ <sup>64</sup> Cu]Cu-1C1m-Fc resulted in an effective dose of 0.05 mSv/MBq. Absorbed dose (AD) extrapolation for the [ <sup>177</sup> Lu]Lu-1C1m-Fc indicated that the AD of 2 Gy and 4 Gy to the red-marrow and total-body can be reached with 5-10 GBq and 25-30 GBq of therapeutic activity administration respectively depending on applied dosimetry method. Dosimetry extrapolation methods provided significantly different absorbed doses in organs. Dosimetry properties for the [ <sup>64</sup> Cu]Cu-1C1m-Fc are suitable for a diagnostic in-human use. The therapeutic application of [ <sup>177</sup> Lu]Lu-1C1m-Fc presents challenges and would benefit from further assessments in animals' models such as dogs before moving into the clinic

Assessment of a fully 3D Monte Carlo reconstruction method for preclinical PET with iodine-124

International audienceIodine-124 is a radionuclide well suited to the labeling of intact monoclonal antibodies. Yet, accurate quantification in preclinical imaging with I-124 is challenging due to the large positron range and a complex decay scheme including high-energy gammas. The aim of this work was to assess the quantitative performance of a fully 3D Monte Carlo (MC) reconstruction for preclinical I-124 PET. The high-resolution small animal PET Inveon (Siemens) was simulated using GATE 6.1. Three system matrices (SM) of different complexity were calculated in addition to a Siddon-based ray tracing approach for comparison purpose. Each system matrix accounted for a more or less complete description of the physics processes both in the scanned object and in the PET scanner. One homogeneous water phantom and three heterogeneous phantoms including water, lungs and bones were simulated, where hot and cold regions were used to assess activity recovery as well as the trade-off between contrast recovery and noise in different regions. The benefit of accounting for scatter, attenuation, positron range and spurious coincidences occurring in the object when calculating the system matrix used to reconstruct I-124 PET images was highlighted. We found that the use of an MC SM including a thorough modelling of the detector response and physical effects in a uniform water-equivalent phantom was efficient to get reasonable quantitative accuracy in homogeneous and heterogeneous phantoms. Modelling the phantom heterogeneities in the SM did not necessarily yield the most accurate estimate of the activity distribution, due to the high variance affecting many SM elements in the most sophisticated SM

Clinical radioimmunotherapy-the role of radiobiology

Conventional external-beam radiation therapy is dedicated to the treatment of localized disease, whereas radioimmunotherapy represents an innovative tool for the treatment of local or diffuse tumors. Radioimmunotherapy involves the administration of radiolabeled monoclonal antibodies that are directed specifically against tumor-associated antigens or against the tumor microenvironment. Although many tumor-associated antigens have been identified as possible targets for radioimmunotherapy of patients with hematological or solid tumors, clinical success has so far been achieved mostly with radiolabeled antibodies against CD20 ( 131I-tositumomab and 90 Y-ibritumomab tiuxetan) for the treatment of lymphoma. In this Review, we provide an update on the current challenges aimed to improve the efficacy of radioimmunotherapy and discuss the main radiobiological issues associated with clinical radioimmunotherapy. © 2011 Macmillan Publishers Limited. All rights reserved