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Mechanism of toxicity of aluminium-based adjuvant (ABA) nanomaterials

Christopher Exley

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Medical Research Council (MRC)
Aluminium-based adjuvants (ABA) are micron-sized materials which upon dissolution in interstitial fluid form nanometer-sized particles with biological effect. Their mechanism of action in improving the immune response remains to be fully elucidated and these nanomaterials are excellent models for understanding nanotoxicity. The latter is important in that the number and amount of nanomaterials to which humans are exposed during their everyday lives are burgeoning without any sure knowledge of their ultimate biological fate and safety. Understanding of the mechanisms of toxicity of nanomaterials in humans could be determined from a thorough understanding of how ABA enhance the immune response. In preliminary research in which phagocytosing cells were exposed to ABA we identified mitochondria as potential targets of ABA mediated nanotoxicity. Cell fractionation suggested that mitochondria accumulate ABA nanomaterials. Herein we combine a thorough examination of the physico-chemical properties of both current and novel ABA with detailed investigations of their biological effect in phagocytosing cells and in an established rodent model of malignant brain tumours. Physico-chemical characterisations will enable an understanding of the bioinorganic chemistry of these materials in biological milieu which will be used to understand their cellular toxicity and ultimately their application to adjuvant-based immunotherapy. We will apply state-of-the-art fluorescent labelling methods such that we will be able to follow the trafficking of ABA nanomaterials both in cell culture and in an animal model. Once a detailed understanding of the toxic mode of action of ABA is obtained the idea is to optimise similar materials and exposure regimes both for the effective and safe use of ABA in vaccinations programmes but also for targetting cell death in malignant brain tumours which could become a therapeutic off-shoot of an improved understanding of the toxicity of ABA nanomaterials.

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