The main objective of this project is to establish a new therapeutic approach for glioblastoma (GBM) based on the use of RNAi technology (more specifically siRNA) to reduce the cellular levels of proteins involved in the survival and proliferation of tumor cells, making them more susceptible to anticancer drugs and/or radiation.
The siRNA will be administered by two different families of state-of-the-art multifunctional nanocomposites, comprising β-cyclodextrin and dihydropyridine derivatives. The nanocomposites will be modified in their structure and chemical surface to efficiently perform the tasks required to target intracerebral GBM xenografts: crossing the blood-brain barrier, targeting tumor cells, or imaging tumors.
The siRNAs will be designed to deactivate key proteins in signaling pathways involved in GBM cell proliferation and survival, such as Ras/Raf/ERK complexes or mTOR.La transfection efficacy of nanocompounds will be tested in vitro on isolated GBM cells obtained from the patient’s tumor dissociation from the patient’s GBM organoids obtained from tumor tissue resected during therapeutic surgery.
After showing a high transfection efficiency in isolated GBM cells, the in vivo toxicity of the nanocomposites will be studied by determining different biochemical parameters in the plasma of mice that will provide information on lipid, renal and hepatic biochemical profiles.
In addition, possible additional pharmacological/toxic actions of the nanocomposites will be studied. Nanocomposites lacking in vivo toxicity will be used to deliver siRNA to syngeneic xenografts in mice or to patient-derived GBM xenografts in immunodeficient mice. The use of tumours from patients with GBM and the correlation with the clinical data of these patients will increase the relevance of the results obtained in this project and the probability that, in due course, they will reach the clinical setting.
