Intranasal delivery of carbon nanotubes to the brain parenchyma: preliminary pharmacokinetic and pharmacodynamic evidences

Carbon nanotubes (CNTs) are gaining increasing importance in the biomedical field. Among several biomedical applications, they represent a versatile tool to deliver or increase the yield in delivering therapeutics to selected targets. CNTs have proven to be attractive as potential therapeutics or vehicle to target blood-brain-barrier-protected brain cells. The possibility to deliver drugs to the brain parenchyma by the olfactory route has been recently reported. To date, the delivery of CNTs to the brain by intranasal administration has never been attempted.The main aim of the present study was a preliminary characterization of pharmacokinetic and pharmacodynamic parameters of two types of carbon nanotubes (CNTs) delivered to the brain parenchyma via the novel and unexplored olfactory route. To achieve this general aim, we studied tissue and cellular distribution of intranasally-delivered multi-walled carbon nanotube-11 (MWNT-11, not electroconductive) and annealed-MWNT-12 (aMWNT-12, electroconductive) in healthy and early diabetic rats, the latter known to be affected by mild cognitive impairment and neurodegeneration. We also attempted a preliminary characterization of the effects of CNTs on the metabolism of the neurotrophin nerve growth factor (NGF), known to play a central role in the development and progression of major neurodegenerative diseases, including diabetic encephalopathy.Our study, mainly performed by confocal microscopy, revealed that intranasally-delivered CNTs consistently diffuse into the brain parenchyma, reaching at least medial regions of the brain. CNTs were internalized by both neurons and glia, both expressing the GABA-ergic marker GAD, in all the regions reached by the nanomaterial. The tissue and cell distribution of MWNT-11 and aMWNT-12 in the brain of healthy and diabetic rats did not present qualitative macroscopic variances. However, significant differences were found when the effects of the treatments were evaluated on mNGF/proNGF protein levels and the glial/neuronal phenotypes in the hippocampus, caused both by the induction of diabetes and by the different CNT used as therapeutic. Overall, our data indicated that aMWNT-12 was able to elicit a modulation of the neurotrophic milieu and a control over the surrounding reactive gliosis similar to what observed when other neuroprotective therapies were applied in the same experimental model.Overall, our preliminary studies strongly support the need for building a clear and complete description and knowledge of the pharmacokinetic and pharmacodynamic features of CNTs after their delivery to the brain via the intranasal route.