[en] Full text of publication follows. Although only palliative, external beam radiation remains to date the standard treatment of dramatic brain glioblastoma (GBM). Radiotherapy effectiveness is indeed largely limited by resistance mechanisms combining intrinsic properties of tumour cells to the influence of the microenvironment in which they develop (e.g. hypoxia). The recent discovery of stem-like cancer cells (SLCC) in GBM supports the presumption that the failure of conventional antitumor strategies could be attributed to a problem of target cells. Thus, the present work deals with the development of a new-targeted internal radiotherapy to radio-resistant SLCC through the use of nano-carriers loaded with α- or β- radiation emitters. As CXCR4 receptor has been associated with radio-resistance and with SLCC occurrence, we focused on the targeting of these proteins in a human GBM models known to express it: A172. We primarily developed 50 nm lipid nanocapsules (LNCs) functionalized with monoclonal antibodies (mAbs) directed against CXCR4 (or iso-type control) [Ref.1]. LNCs will then be combined to "1"8"8Re (beta emitter) and "2"1"1At (α-emitter) for further evaluation. By using blocking antibodies, our investigations merged the interest of targeting SLCC associated epitopes to the one of inhibiting CXCR4 signaling pathways to overcome radioresistance. In line with this, by using immunofluorescence flow cytometry, we found that CXCR4 expression is correlated with radiation doses: we found 41% expression when are radiated at 32 Gy versus 10% expression when they are radiated at 0 Gy. Finally, new encapsulation of "1"2"5I (β-emitter and halogen), which will help for the development of "2"1"1At (halogen), has been developed. Preliminary results show a relatively stable SIB encapsulation over time in different medium. Efficacies of β- versus α-nano-carrier based radio-therapies will then be compared in vivo after ortho-topic implantation of human GBM cells in immuno deprived SCID mice and loco-regional infusion of the treatment. Reference: Ref.1: Bourseau-Guilmain, E.; Bejaud, J.; Griveau, A.; Lautram, N.; Hindre, F. et al. Development and characterization of immuno nano-carriers targeting the cancer stem cell marker AC133. International Journal of Pharmaceutics. (authors)

[en] The rhenium-188 (¹⁸⁸Re) presents a great interest by its chemical and physical properties near the ^99mTc and its mode of production (generator ¹⁸⁸W/¹⁸⁸Re; T=16.9 h). Its emission R- (2.12 MeV) makes of it a good candidate for the radiotherapy, while its gamma radiation (155 KeV) offers an imaging possibility.The objective of this study was to evaluate the efficiency of a multi times intra skull giving of 2.8 MBq of N.C.L.¹⁸⁸Re-S.S.S. on a model of glioblastoma of rat. Our results show the interest of an internal radiotherapy fractionated in the heart of a model of glioblastoma of rat. (N.C.)

[en] Lipid nano-capsules loaded with rhenium-188 (LNC¹⁸⁸Re-SSS), used for fractionated internal radiation in a glioblastoma rat model, led to important increase of survival with 83% of long-term survivors. As already observed with ionizing radiation, the development or potentiation of an immune response could explain these results. The aim of this study was therefore to characterize and better understand the various factors involved in this reaction. After stereotactic implantation of glioma 9L cells in the right striatum of fisher female rats, a local fractionated administration of LNC¹⁸⁸Re-SSS (2.8 MBq) at D6 and D12 was realized. Two types of injection were used: bolus and convection-enhanced delivery (CED). Results demonstrated increase of cytokine (IL-2 and IFN_γ) peripheral production after internal radiation. Recruitment of immune and inflammatory cells (dendritic cells, CD4, CD8, NK, macrophages, micro-glia) is observed into the tumoral site. Moreover, increased expression of MCH class I and MCH class II was also demonstrated. Finally, an increase of survival up to 32% compares to control rats with 25% of long-term survivors after re-challenging showed an immunization process

[en] Full text of publication follows. Aim: Glioblastoma (GBM) is the most frequent cancer of the nervous system and therapies currently used cannot treat definitively this disease. By the way of NucSan (Nuclear for health) program which supports research development about the use of radio pharmaceutics in oncology, the aim of the proposed work is to provide evidences that internal radiotherapy through lipid nanocapsules loaded with Rhenium-188 (LNC¹⁸⁸Re-SSS) is an alternative therapeutic strategy for GBM that can be translated to human medicine. Previous works have shown a remarkable efficiency of this tool among syngeneic rats linked with local and peripheral recruitments of the immune system's effectors. In this context, two animal models have been chosen to validate the feasibility of this new innovative therapy design (LNC¹⁸⁸Re-SSS stereotactic injection). Materials and methods: the syngeneic six weeks old C57BL/6J female mice were treated 6 or 12 days after stereotactic GL261 cells implantation, by a single injection of increasing activities of LNC¹⁸⁸Re-SSS (0,925; 1,85 and 2,7 MBq/5μl). MRI was used to follow tumor progression to determine the mass volume through the selection of regions of interest. The increased median survival time (IMST) was also assessed for treated mice versus control mice (stereotactic injection of saline solution). For long time survival animals (3 times the median survival time), they were rechallenged through the same procedure in the other hemisphere. The brachy-cephalic dog bearing spontaneous tumor will lead to additional evidences to specifically highlight the potential of this innovative technology for GBM treatment. In order to validate procedures of intracerebral injections, a stereotactic head frame specially designed for dog has been conceived which allow both images acquisition (MRI-SPECT and PET) and the achievement of biopsies. Results/Perspectives: as previously observed on rat models, the preliminary data show interesting results on treatment efficiency in GL261 mice model with the long time survival animals assessed by the absence of tumor progression (IMST: 41%). Thanks to the dog head frame accuracy, brain biopsy targeted by pre/post-surgery MRI has been validated. These two preclinical models will give us additional evidences for a translational approach with the help of CGO-2012 (IRAD) and ANR-12-EMMA-003301 Radiohead projects. They aim at collecting data on in vivo feasibility and efficiency of LNC¹⁸⁸Re-SSS for GBM treatment, especially in a spontaneous model linked with immune response. Finally, the objective of this work is to set up a phase I/II clinical trial. (authors)