Delivery of nanoparticles across the blood-brain barrier for the treatment of invasive glioblastoma

Treatment of glioblastoma, a brain cancer with a high mortality rate, is severely complicated by difficulties associated with delivering therapeutics to the central nervous system (CNS) and rapid, diffuse invasion of the tumour cells throughout the brain. Nanomedicine is believed to have the potential to overcome challenges with therapeutic delivery. However, the field lacks standardisation which complicates elucidating nanoparticle properties that facilitate safe, effective delivery to the brain. To address this, nanoparticles were synthesised from 5 materials across 3 sizes. These particles were characterised using standard techniques in water, to determine the properties of the newly synthesised nanoparticles, and in media and serum, to clarify how nanoparticle properties change in physiological environments. The nanoparticles were then tested on a blood-brain barrier (BBB) model which was prepared using a method of serum starvation that resulted in barrier resistances that closely resemble the native BBB (3000-4000 Ω.cm 2 in vitro, 2000-5000 Ω.cm 2 in vivo). It was found that the properties of nanoparticles, in particular nanoparticle zeta potential, determined in media, not water, correlated well with the interaction between nanoparticles and the BBB including nanoparticle permeability and effects on neurovascular cells viability. In particular, Fe2O3 nanoparticles, which have media-based zeta potentials between -10 and -12 mV, are capable of good BBB penetration with minimal changes to cell viability. These nanoparticles could be useful for the delivery of therapeutics to glioblastoma. However, the reasons for tumour cell invasion must still be addressed. The role for biomechanics, in particular compressive loading, brought about in vivo by increased cranial stresses resulting from tumour growth, were investigated. The migration speed of glioblastoma cells significantly increased in response to compressive loading. This represents a potential avenue for treatment that has not previously been explored. The use of nanoparticles to inhibit glioblastoma invasion, stimulated by compressive loading, could help to improve the survival rates associated with this deadly cancer.