Abstract
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.
Comparison of Multiple Parameters Obtained on 3T Pulsed Arterial Spin-Labeling, Diffusion Tensor Imaging, and MRS and the Ki-67 Labeling Index in Evaluating Glioma Grading
