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Title: The development of carbon nanotubes as cancer therapeutics : from pharmacokinetics and toxicology to therapy
Author: Ali-Boucetta, Hanene
ISNI:       0000 0004 0123 5258
Awarding Body: University College London
Current Institution: University College London (University of London)
Date of Award: 2010
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The central hypothesis for this thesis is that functionalised carbon nanotubes (CNT) can be developed for cancer therapy. This was based on current proof- of- principle studies shown that CNT have an extraordinary ability to cross the plasma membrane and deliver therapeutic molecules such as protein and DNA independent of the functional group and the cell type in addition to their unique physicochemical properties. At the same time it is well known that the therapeutic efficacy of many potent and promising anticancer drugs has been limited due to their low water solubility, increased drug resistance and high cytotoxic side effects. Therefore, it was hypothesised that the engineering of novel CNT; anticancer drug hybrids represent a valuable alternative to achieve enhanced cellular uptake and increased efficacy of such therapeutic agents. The aim of this thesis was to elucidate the important and critical parameters in CNT pharmacokinetics and toxicology and to take this further into establishing effective CNT nanovectors for cancer therapeutics as gaps still exist in the accurate understanding of CNT impact and interaction with the biological milieu. This was achieved by: (1) investigating the effect of surface functionalisation, coating and dispersion properties on CNT biodistribution after intravenous administration; (2) studying the interference between CNT and the widely used cytotoxic assays (MTT, LDH and Annexin V/Pl) and subsequently developing a reliable toxicity assay; (3) exploring the effect of chemical functionalisation strategies on the toxicity of CNT in vitro and in vivo; (4) evaluating the cellular uptake and efficacy of CNT: Doxorubicin complexes and CNT-Methotrexate constructs both in in vitro cell monolayers and in vivo tumour models. It was found that the biodistribution of CNT is highly dependent on their physicochemical characteristics mainly the dispersion properties and individualisation of the CNT. It was also concluded that the systemic administration of CNT is still in its infancy and that focus at this stage should only be on local administration since RES organ uptake is highly observed with CNT. In addition, as hypothesised CNT were found to interfere with the MTT, LDH and Annexin V/ PI assays and based on the pitfalls of those assay we have developed a reliable cytotoxic assay. Based on the developed assay, chemically functionalised CNT were found non-cytotoxic compared to polymer coated CNT. Moreover, the in vivo toxicological profile of chemically functionalised MWNT was further investigated using a structure-activity paradigm of toxicity based on the direct exposure of the abdominal cavity of mice to CNT. It was found that chemical functionalisation strategies that debundled and disaggregated CNT led to a sharp reduction of their effective length and completely alleviated the asbestos-like pathogenic behavior observed with their long pristine counterparts. The engineering of CNT for use as cancer therapeutics was also achieved using CNT: Doxorubicin complexes and CNT-Methotrexate constructs. Both novel nanohybrids showed a better in vitro cytotoxic activity compared to the drug alone especially when a tetrapetptide linker was introduced with the CNT-Methotrexate constructs. However, no therapeutic efficacy or tumour reduction was observed in vivo using tumour models compared to the drug alone after intra-tumoral administration. Overall, key factors in CNT biodistribution together with the in vitro and in vivo toxicological profile of chemically functionalised MWNT were reliably determined and thereafter functionalised MWNT were developed as delivery systems for cancer therapeutics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available