WP7 – Nanocarrier-based drug delivery for next generation glioblastoma therapy
Success will have substantial societal, clinical and economic benefit. Ultimately, the outcome will lead to the development of a new therapeutic strategy that will enable the use of both Auger radiotherapy as well as other therapeutic compounds in treating and potentially curing humans with glioblastomas, revolutionizing the therapy of this disease.
We recently demonstrated high efficacy of locally delivered Auger radiotherapy against glioblastoma (GBM) in rat models, leading to 100% survival of the rats. However, later studies in the larger pig brain resulted in rapid wash-out of the compound, hampering clinical translation of this promising treatment. To overcome this major pharmacokinetic challenge, we have obtained proof-of-concept results that nanosized carriers (NCs) administered directly to rat brains by convection enhanced delivery (CED) distributes efficiently and are well-retained.
This strongly indicates that delivery by NCs is a viable road to therapeutic success with our compound in humans. However, very limited knowledge exists about the behavior and biokinetics of nanoparticles delivered by CED in the brain parenchyma – either with or without prior tumour resection. This is especially true in large, non-rodent GBM tumours where tissue penetration can be hampered by necrotic regions, increased intratumoural pressure or the resection cavity. Such knowledge is essential for translating NCs for clinical use against brain cancer, and consequently for making our therapy available for human patients.
Investigate the biodistribution and pharmacokinetic properties (volume of distribution, retention, excretion, metabolism) of three different NC designs covering the entire span of biomedically relevant sizes in our established GBM model in pigs.
To simulate the clinical situation and thus, maximize the translational design, the studies are performed in both tumour-bearing and tumour-resected pigs and compared. The NCs will be: Liposomes at 100 nm (large), gold nanoparticles at 50 nm (mid-sized), and polymeric micelles at 10 nm (small), all of which will be radiolabeled and pegylated. This will allow the determination of the optimal nanocarrier design. In short, minipigs will be implanted with human glioblastoma cells. Upon tumour formation a CED system is implanted. This is followed by infusion of radiolabeled NCs intratumoural and the distribution and pharmacokinetics of the NCs are then evaluated by dynamic PET/MRI and by post-mortem analyses.
Determination of the most optimal nanoparticle design for successful drug delivery by CED in a large-brain GBM model.