Shuttling through the Blood Brain Barrier using Carbon Nanoneedles

A significant proportion of the population are affected by diseases of the brain, many of which have limited drug treatment. Such diseases are often difficult to clinically diagnose and treat due to the limitations of brain access. One of the principle obstacles in drug development is brain delivery of the drugs or imaging agents, that can treat the disease or enhance its diagnosis. Recently, ultra small tubular like nanomaterial made of carbon called carbon nanotubes has been developed which could serve as "rafts" that could help transport drugs into the brain or could facilitate imaging of the brain. However, at present there is lack of information about the ability and mechanisms by which these nanotubes can penetrate into the brain through the blood brain barrier. This project will utilise a cellular model of this tight membrane to investigate how these nanotubes cross the endothelial brain membrane and whether they affect its integrity.

Targeted drug delivery across the blood brain barrier (BBB) to the central nervous system is a large challenge for the treatment of neurological disorders. Drug delivery systems that cross the BBB without disrupting it would also have many applications for brain cancer diagnostic and other diseases, e.g. Alzheimer's disease. There still remains a pressing need for improved nanoparticle delivery systems to target drugs across the BBB. Functionalized carbon nanotubes (CNTs) are receiving increasing attention as vehicles for the delivery of diagnostic and therapeutic agents. The delivery properties of CNTs derive from the potential to deliver a drug by heterogeneously functionalizing their surface and also their ability to traverse the plasma membrane, promoting the cellular uptake of small molecules. However, there is essentially no mechanistic data at the level of individual CNTs to characterise their fundamental interaction with endothelial cells or how this interaction is modified by CNT surface chemistry and targeting to specific BBB receptors such as transferrin receptor or low density lipoprotein receptor-related protein 1. This project aims towards the evaluation of the BBB penetration capacity of novel f-CNT carriers using an in vitro BBB model employing porcine brain endothelial cells (PBECs) chosen due to its high transendothelial electrical resistance when cultured as a monolayer without astrocytes (>300 ohm.cm2) and good expression of the most important drug efflux transporters and P-glycoprotein. f-CNT will be fluorescently labelled or conjugated to a radioactive tracer to allow for qualitative and quantitative measurement of uptake or BBB permeation. Insights into these mechanisms will be essential to guide the development of CNT vectors to deliver drugs across the BBB to the central nervous system for the treatment of neurological disorders.

This project will have an impact in academia and industry and will address all those interested in brain delivery, blood brain barrier biology and nanomedicine. Such a collaborative project promises to bring about a long-term benefit to the development of UK and European science and its clinical translation. It is relevant to pharmaceutical and medical companies interested in developing novel therapeutic approaches to the brain. The research aims to improve and expand brain delivery options to enhance the quality of life for UK and European citizens. It has the potential to contribute to knowledge transfer among the different national and European collaborators who are experts in their field. The development of nanopharmaceuticals is an emerging multidisciplinary area and research within a multidisciplinary team is mandatory for progress in the field. It is expected that a number of additional national, EU or independently funded collaborative projects will follow the developments achieved by this project. After fundamental understanding of how permeation processes take place, future funding for further clinical testing and commercialisation of the novel nanotube-based brain delivery systems along will be sought along with an industrial partner. Two highly skilled PDRA researchers will result from this work, ripe for employment in pre-clinical, clinical, industrial, or academic sector.