Background Glioblastoma multiforme (GBM) is a very aggressive tumor with no cure up to date. Current treatments (irradiation therapy and chemotherapy after surgery) provide a survival of 14 months post diagnosis. Resistance to therapies are connected to a subset of GBM cells, the cancer stem cells (CSCs), able to survive in a quiescent state and exhibit features which are central in tumor recurrence and malignancy (e.g. invasiveness, resistance to drug, differentiation into endothelial vasculature cells). A first nanoparticle (NP) based approach for the GBM has reached the clinic in Germany. The heat generated by magnetic NPs under an oscillating magnetic field, the so-called magnetic hyperthermia (HT), have provided an overall survival of 23 months in GBM patients when associating magnetic HT to radiotherapy. However, due to the high dose of NPs, the current HT approach does not allow the follow up of the tumor by magnetic resonance imaging (MRI) after HT. Hypothesis There is a clear need to identify therapies which are more effective against GBM and to redesign more efficient therapies against GBM CSCs. Also, having the chance to monitor by MRI the tumor follow-up after magnetic HT is crucial to advance the current state of magnetic NP-based HT. To fulfill these challenges advanced magnetic NP platforms will be developed to combine multiple approaches to fight GBM cancer. Aims We will prepare magnetic NP-based platform able to perform i) magnetic HT, ii) heat-mediated drug delivery and iii) GBM tumor targeting. Experimental Design The magnetic based platform will include: i) the last generation of magnetic nanoparticles with state of the art performance as heat foci under an externalmagnetic field; ii) Decorate the magnetic-NPs with thermo-responsive polymers able to sense temperature changes and promote remote polymer activation with release of therapeutic agents associated to them. iii) The GBM tumor targeting units to keep the platform at the tumor and avoid NP clearance. Finally, NP heat + drug effects will be studies first on mammosphere generated by GBM CSCs and later on the same cells implanted in mice for tumor targeting, NP degradation and therapeutic efficacy evaluation. Expected Results Expected results include: a) Synthesis of magnetic NPs; b) their functionalization with thermo-responsive polymers or porous silica for drug encapsulation; iii) drug release. (c) NP functionalization with tumor targeting units; d) Loading of GBM chemo therapeutic agents within the magnetic NP platform and drug release study. e) In vitro test of tumor targeting and drug toxicity. (f) 3Din-vitro assays for evaluating combinatorial effects of drug release and heat effects on GBM CSCs. (g, h) In-vivo therapeutic efficacy and targeting studies. Impact On Cancer Having identified drawbacks of the current magnetic NPs to GBM, and the knowledge gap in effects of magnetic heat therapy in combination to drug therapy on GBM CSCs, this project will build a step-by-step systematic knowledge and it will potentially reveal new therapeutic strategies to treat GBM. Fundamental concepts of drug design based on NPs, NP-CSC interaction, GBM tumor targeting will provided together with new 2D and 3D in-vitro models and preclinical data for GBM treatment based on nanoparticle platform.