Drug resistance in cancer patients is a currently growing worldwide problem that affects nearly 50% of glioblastoma multiforme patients who receive the chemotherapy drug Temozolomide (TMZ) as the main treatment. This critical issue needs to be addressed, considering that in this type of pathologies, time for intervention is limited by the short life expectancy (12-14 months). This has led to the need for more robust in vitro models to evaluate the performance of the treatments and possible resistance prior to clinical testing. Therefore, the present work seeks to propose and evaluate the performance of a 3D spheroid model for glioblastoma such that a greater similarity to native tumor tissue is intended in terms of structure and drug diffusion properties. This model was compared to traditional 2D cell cultures and demonstrated significant differences in cell viability after treatment with TMZ. This was attributed to the influence of cell packing density of the formed spheroids on the TMZ's penetration. The obtained results confirmed the low penetration of TMZ on spheroids, which largely explains the observed resistance clinically. An attractive alternative to improve penetration is the use of nanovehicles for delivery, as they have demonstrated superior cell penetration abilities when functionalized with biological and synthetic cellpenetrating agents. We have functionalized magnetite nanoparticles with the peptide Buforin-II to produce nanobioconjugates with remarkable membrane translocation potency. We propose to employ these nanobioconjugates to deliver Hydroxyurea, a compound with superior antitumor activity.