Translational Evaluation of a Dodecaborated Albumin Conjugate With Maleimide as a Boron Delivery System for a Neutron Capture Reaction to an F98 Rat Glioma Model

Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing. In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 hours after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 hours after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 hours after MID-AC administration. MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.

P11.40 Development of an implantable multifunctional biodevice (GlioGel) in the treatment of recurrent glioblastoma

BACKGROUND Glioblastoma (GBM) is a devastating disease with a median survival of 14–16 months. This poor prognosis can be explained by 3 factors. First, the infiltrative nature of the disease prohibits a complete removal of the tumor. Second, some of the tumor cells are brain tumor stem cells, which are highly migratory and highly resistant to treatments. Finally, the presence of the blood-brain barrier prohibits entry of therapeutics. This situation implies that new treatment approaches must be directed toward the infiltrated brain surrounding the resection cavity. To bypass this problem and improve the potency of adjuvant treatment, we have designed a new “GlioGel-device” that will have the ability to: 1- attract the migrating tumor cells into or nearby the device, and 2- subsequently deliver chemotherapy to the locally pooled tumor cells and 3- irradiate these cells with radioisotopes embedded in the GlioGel. MATERIAL AND METHODS In vitro proof of principle of chemoattraction was investigated by agarose drops method releasing chemokines molecules (CCL2, CCL11, CXCL10) with F98 and U87MG GBM cells. In vivo experiments evaluated the efficiency of chemokines and doxorubicin released by the implanted GlioGel on the tumor behaviour in our Fischer-F98 rat glioma model. An histology of tumour behaviour exposed to chemokines and survival of GBM rats treated with doxorubicin were analysed. RESULTS In vitro preliminary results for chemoattraction assays show that up to 2 times more cells invade the gel when it releases chemoattractant compared to PBS. The In vivo chemotherapy experiments with a fast, medium and slow release of doxorubicin from the GlioGel show that a local dose that represent a 1300-fold smaller dose than a normal intravenous systemic dose gave a significant reduction in tumour growth (median survival) compared to a control group. We investigated the effect provided by the GlioGel impregnated with chemokines on tumor cells migration, after implantation in the Fischer-F98 rat glioma model. CONCLUSION This preliminary study shows the ability of GlioGel releasing chemokines and doxorubicin to respectively attract and kill orthotopic glioblastoma cells. These encouraging results will be completed with a combination of short-range (high LET) radiation by embedded radioisotope into the GlioGel aiming for synergistic combination to eradicate as much tumour cells as possible, while limiting systemic side effects.

Detection of Remote Neuronal Reactions in the Thalamus and Hippocampus Induced by Rat Glioma Using the PET Tracer Cis-4-[18F]Fluoro-D-Proline

After cerebral ischemia or trauma, secondary neurodegeneration may occur in brain regions remote from the lesion. Little is known about the capacity of cerebral gliomas to induce secondary neurodegeneration. A previous study showed that cis-4-[18F]fluoro-D-proline (D- cis-[18F]FPro) detects secondary reactions of thalamic nuclei after cortical infarction with high sensitivity. Here we investigated the potential of D- cis-[18F]FPro to detect neuronal reactions in remote brain areas in the F98 rat glioma model using ex vivo autoradiography. Although the tumor tissue of F98 gliomas showed no significant D- cis-[18F]FPro uptake, we observed prominent tracer uptake in 7 of 10 animals in the nuclei of the ipsilateral thalamus, which varied with the specific connectivity with the cortical areas affected by the tumor. In addition, strong D- cis-[18F]FPro accumulation was noted in the hippocampal area CA1 in two animals with ipsilateral F98 gliomas involving hippocampal subarea CA3 rostral to that area. Furthermore, focal D- cis-[18F]FPro uptake was present in the necrotic center of the tumors. Cis-4-[18F]fluoro-D-proline uptake was accompanied by microglial activation in the thalamus, in the hippocampus, and in the necrotic center of the tumors. The data suggest that brain tumors induce secondary neuronal reactions in remote brain areas, which may be detected by positron emission tomography (PET) using D- cis-[18F]FPro.