Dos Santos Nunes, Antonio Augusto Lucas; (2012) Exploring carbon nanotube pharmacology and transport to the brain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The use of nanomaterials may contribute to our understanding of the central nervous system (CNS) and the development of novel therapeutic strategies for neurological interventions. Carbon nanotubes (CNT) are among the most promising types of novel nanomaterials that have attracted attention because of their extraordinary properties such as high electrical and thermal conductivity. The development of CNT functionalisation chemistries has led to their enhanced dispersibility in physiological media and broadened the spectrum for their potential biological applications. This thesis aimed to enable the development of CNT-based delivery system potentially able to transport therapeutic or diagnostic agents to the brain, offering significant benefits for a variety of currently untreatable neurophatologies, such as stroke or Parkinson's disease. Different types of chemically functionalised multiwalled nanotubes (f-MWNT) constructs were used and compared in this work. Amino functionalised MWNT (MWNT- NH3+), oxidised and amino functionalised MWNT (oxMWNT-NH3+) and amidated MWNT (oxMWNTamid-NH3+) have been studied. Oxidation of the material led to the introduction of carboxyl groups and the corresponding shortening of the nanotubes. The central question that this thesis asked was the determination of the extend of MWNT transport into the brain and the structure-function relationship that controlled this. Multiple routes of administration were studied in relation to the brain translocation of the nanotubes: i) intravenous, ii) intra-nasal, and iii) stereotactic administration. The biodistribution profile of functionalised carbon nanotubes (f-CNT) after intravenous administration was investigated in relation to the physicochemical properties of CNT, such as dispersibility and chemical functionalisation. It was found that by changing the degree of surface functionalisation of CNT, it was possible to control their organ distribution and blood clearance profile. A series of f-CNT obtained from the same starting material were chemically modified and showed that CNT exhibiting less surface functionalisation favoured liver accumulation. Liver accumulation was significantly reduced by increasing the degree of chemical functionalisation, while renal excretion showed an opposite trend. Although it is considered extremely important for the design of novel CNT-based diagnostics and therapeutics, this route of administration was found to be limited for neurological applications due to poor brain uptake levels. Therefore, the work focused on alternative (intra-nasal) and local (stereotactic) routes to examine transport into the brain. Intra-nasal administration constitutes a feasible delivery route to the brain, avoiding limitations imposed by the lack of blood brain barrier (BBB) permeation of systemic administrations and the invasiveness of stereotactic injections. Evidences obtained in this thesis illustrates that nasal route can offer an efficient strategy to deliver f-CNT into the brain. The unique properties of CNT were expected to facilitate the translocation from the nasal cavity to the brain. The results suggested noticeable differences in the level of nanotube uptake and localisation within the brain tissue, and that these are highly dependent on their chemical functionalisation. The brain uptake of MWNT-NH3+ was demonstrated and related to the ability of nanotubes to remain for an extended period at the nasal cavity. Our results indicated that the olfactory bulb and brainstem were the main regions within the brain that the nanotubes resided, mostly likely via translocation through the trigeminal nerve system. These studies highlighted the potential of f-CNT as a brain delivery system through the nasal route. Finally, a closer insight into the interaction of f-CNT with the neural tissue was conducted after local stereotactic administration. Again, surface functionalisation was found to play an important role in the localisation, transport and intracellular distribution patterns once within the neural tissue, as significant differences were observed between the different constructs. All f-CNT were uptaken by different neural cells types, such as microglia and neurons. However different patterns of cellular internalisation and intercellular fate were observed between the constructs. Transmission electron microscopy (TEM) of the brain sections of the vicinity of the injection site suggested that MWNT-NH3+ were more individualised and dispersed. Interestingly, the fate of MWNT-NH3+ on the longer term (14 days post-injection) also revealed the previous unreported evidence of partial degradation of chemically functionalised MWNT in vivo following internalisation within microglia after direct stereotactic injection in the motor cortex. Overall, this thesis offered evidence and the impetus for further investigations of the critical parameters that will determine the kinetics of CNT translocation in the brain tissue and explored some of the effects of CNT interactions with the neuronal tissue.

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