Final Report Summary - CNTBBB (Targeting potential of carbon nanotubes at the blood brain barrier)
Parkinson's disease (PD) is a debilitating neurodegenerative movement disorder that is projected to rise in incidence due to a rapidly ageing world population. There is a pressing need for the development of efficient delivery systems with the ability to enhance cellular uptake of existing drugs. Engineered nanoparticles are gaining interest as therapeutic drug carriers across the blood brain barrier (BBB). However, there remains an urgent need for improved targeted nanoparticle (NP) delivery systems to deliver drugs across the BBB. The ERC grant has evaluated whether functionalized carbon nanotubes (f-CNTs) can be utilized as delivery vehicles for diagnostics and the delivery of therapeutic agents and also their biopersistance/bioreactivity in the brain. The program also evaluated the cell targeting efficacy, long term fate and safety of other classes of nanostructures in the brain and other organs. The overall goal was to make a step change in our understanding of the fate of nanoparticles inside cells to guide treatment and diagnostics of diseases.CNTBBB has taken a large step forward in improving our understanding the bio-persistence of multiwalled nanotubes and other commercially relevant nanostructures, such as silver nanoparticles in the brain, by analysing the interaction between the highly controlled and well characterized nanomaterials and the BBB, neurons and microglia, the local phagocytic immune cells. We have successfully applied a new method for carbon nanotube (CNTs) functionalisation, developed in-house, which has a significant advantage of minimizing the damage to the nanotube framework, in contrast to traditional acid oxidation routes. This method has allowed us, for the first time, to directly correlate the physicochemistry of these materials to their bioreactivity and interaction with cells in the brain and at the blood brain barrier.CNTBBB has shown that these CNTs can cross the BBB in small amounts and that surface charge is a crucial parameter governing CNT transport across the BBB, with negative charge inducing the highest amount of BBB crossing. None of the f-CNTs altered the health of the brain endothelial cells, neurons or microglial cells, thus this material does not appear to pose a threat to human health. The brain cells were able to break apart and eventually partially degrade the functionalised and individual MWNTs but not aggregates of pristine MWNTs. Thus biopersistance of these materials in the brain relates to their physicochemistry in the extracellular environment. Crucially, we have shown that the extracellular environment (specifically, the presence of proteins, lipids and how they influence the physiochemistry of the nanomaterials etc.) is a key determinant in modulating how the nanomaterials interact with, and are processed by cells. Consequently, we adapted this new hypothesis about the significance of the extracellular environment, to evaluate how nanomaterials interact with lung and breast cancer cells and have shown that it plays a very significant role in reducing and altering subsequent uptake of nanomaterials by cells.CNTBBB has developed new multiscale characterization methods to assess the safety of MWNTs and other classes of engineered nanostructure, notably we have found that silver nanomaterials are nontoxic and have an anti-inflammatory effect on brain cells, since they are able to transform to less reactive silver sulphide nanoparticles. The techniques developed through CNTBBB have been adapted to probe very fundamental questions about how nanomaterials interact with, and are processed by other organs in the body to predict and ultimately control their effects on human health. Importantly, we have found that if silver nanomaterials are accidently inhaled into the lung this material could predispose those exposed to this commercially relevant class of nanomaterial to asthma. Significantly, we used the insight and techniques developed through CNTBBB to design a new targeted class of nanomaterial which is showing much higher amounts (40%) of BBB crossing than previously possible which could be transformative for treatment of PD and other brain diseases.