Exploiting ligand multivalency to selectively target HER2 receptor in glioblastoma

Glioblastoma (GBM) is the most common and fatal primary malignant tumor in the central nervous system. The main genetic alterations involved in GBM regard the PI3K/Atk and the MAPK pathways, which can be activated by the epidermal growth factor receptors (HER), and regulate cell cycle and apoptosis. Indeed, HER receptors overexpression in cancer is a poor prognostic marker and, therefore, is becoming a promising therapeutic target. However, the main obstacles to the delivery of drugs into the brain are the tumor microenvironment and the blood-brain barrier, which make selective targeting not trivial to achieve. In this scenario, polymeric nanoparticles functionalized with selective ligands are emerging as powerful vectors to reach into one of the most difficult organs in the human body. In the present study, we focus on HER2 receptor as a target for drug delivery. Its dimerization with other ligand-bound HER family receptors causes the activation of PI3K and MAPK signaling cascades, leading to uncontrolled growth of cancer cells. The first aim of this work is to investigate the expression of HER2 receptor on primary GBM cells. Then, we try to identify the optimal number of ligands (KCCYSL peptide) against the HER2 receptor and tethered on spherical polymeric nanoparticles. Here we analyse how the ligand multivalency influences the interaction between the nanoparticles and GBM cells, the ability of the ligand to bind HER2, and the effect on the receptor’s biological activity.