Design of Nanocarriers to Deliver Small Hydrophobic Molecules for Glioblastoma Treatment

The aim of this thesis was to develop nanocarriers for efficient delivery of two low molecular weight hydrophobic drugs, apigenin (AG) and a ferrocifen-derivative (FcTriOH) to glioblastoma (GBM) as potential therapeutic strategies. Firstly, two liposomes, a lipid nanocapsule (LNC), and a polymer-based nanocapsule were developed and compared by their physicochemical characteristics, drug loading capacity, storage stability, stability in biological serum, drug release profiles, complement consumption and toxicity. Due to various advantageous characteristics, the LNCs were selected for further optimization. Secondly, the LNCs were surface functionalized by adsorbing a GBM-targeting cell-penetrating peptide (CPP). The CPP concentration increased to significantly enhance LNC internalization in human GBM cells. The uptake mechanisms observed in U87MG cells were: micropinocytosis, clathrin-dependent and caveolin-dependent endocytosis. Moreover, the optimized CPP-functionalized LNCs were internalized preferentially in the GBM cells compared to normal human astrocytes. Additionally, the in vitro efficacy of the AG-loaded and FcTriOH-loaded LNCs was evaluated. The FcTriOH-loaded LNC-CPP showed the most promising activity with a low IC50 of 0.5 μM against U87MG cells. Intracerebral administration of the LNCs in a murine orthotopic U87MG tumor model showed possible toxic effects and the need for dose optimization. Finally, studies in murine ectopic U87MG tumor model showed promising activity after parenteral administration of the FcTriOH-loaded LNCs. Overall, these results exhibit the promising activity of FcTriOH-loaded LNCs as potential alternative GBM therapy strategy.