gms | German Medical Science

Objective: The major obstacles for an effective chemotherapy of glioblastomas (GBM) are the blood-brain barrier (BBB) and serious systemic side effects of the cytotoxic drugs. A new promising strategy could be the delivery of the chemotherapeutics across the BBB to the tumour site encapsulated in microbubbles. The microbubbles will shield the drug from detrimental systemic effects. Low intensity focused ultrasound (LIFU) allows opening of the BBB and a targeted release of the drugs within the brain tumour. Here, we present first data on the synthesis of microbubbles, specifically designed new drugs and the targeted rupture of microbubbles by LIFU.

Methods: Microbubbles were prepared by thin-film hydration of lipids and tested for toxicity on the GBM cell lines GaMG, U87, U138 and U343. In addition, these cells were treated with 6 platinum(II) and palladium(II) complexes conjugated to lipophilic side chains of different length (C1, C8, C10) for 72 h. Cell viability was evaluated with the MTT assay and in real-time utilising the impedance-based xCELLigence DP-System. EC50 values were calculated from both assays.

Results: We synthesized microbubbles ≤2 µm in diameter, which could be disintegrated applying LIFU. Neither the intact bubbles nor the lipids alone showed any toxic effects. In contrast, all six drugs were highly effective. Their EC50 values were far below those of temozolomide (67 µM) and in the range of the EC50 value of the reference drug cisplatin (3 µM). Especially the palladium(II) compound with the C1-chain had a very low EC50 value (<10 µM), while the longer chains and the platinum(II) compounds were less effective (EC50 10–40 µM). The real time proliferation assay of drugs with C1 and C8 side chains revealed an early and concentration-dependent onset of the cytotoxic effect, about 30 h after application.

Conclusion: Microbubbles and highly potent palladium(II) and platinum(II) compounds with low EC50 values were synthesised. Their lipophilic side chains should allow encapsulating them into the microbubbles to develop an effective drug-delivery system for the treatment of GBM. The local concentration of chemotherapeutic agents at the tumour site could be distinctly increased by LIFU, irrespective of their molecular size and BBB penetration capacity.