Abstract

Glioblastoma (GBM) is an intractable malignancy with high recurrence and mortality. Temozolomide (TMZ) and cisplatin (CDDP) based combinational therapy shows promising potential for GBM therapy in clinical trials. However, significant challenges include limited blood-brain-barrier (BBB) penetration, poor targeting of GBM tissue/cells and systemic side effect which hinder its efficacy in GBM therapy. To surmount these challenges, we developed new GBM-cell membrane camouflaged and pH-sensitive biomimetic nanoparticles (MNPs) inspired by the fact that cancer cells readily pass the BBB via reducing the tightness of endothelial cells, and localizing with homologous cells. Our results showed that MNPs can efficiently co-load TMZ and CDDP, transport these across the BBB to specifically target GBM. Incorporation of pH-sensitive polymer then allows for controlled release of drug cargos at GBM sites for combinational drug therapy. Mice bearing orthotopic U87MG or drug-resistant U251R GBM tumour and treated with MNPs@TMZ+CDDP showed a potent anti-GBM effect greatly extending survival time relative to mice receiving single-drug loaded nanoparticles or equivalent doses of free drugs. No obvious side effects were apparent in histological analyses or blood routine studies. Considering these results, our new nanoparticle formulation overcomes multiple challenges currently limiting the efficacy of combined TMZ and CDDP GBM drug therapy and appears to be a promising strategy for future GBM combinatorial chemotherapy.