Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626455
Title: Antibody targeted magnetic nanoparticle hyperthermia for cancer therapy
Author: Kozissnik, B.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Abstract:
Superparamagnetic iron oxide nanoparticles (SPION) are used clinically to improve the sensitivity of magnetic resonance imaging (MRI). A less exploited property of SPION is their ability to generate heat when subjected to an alternating magnetic field, a process called magnetic alternating current hyperthermia (MACH). Hyperthermia has been shown to be a cancer effective treatment modality in the clinic when given together with radio/chemotherapy. However, delivery of sufficient heat to damage tumours without harming healthy tissue remains challenging. The central hypothesis for this thesis is that MACH activated SPION can be used to generate hyperthermia in situ and therefore will have potential to achieve localised hyperthermic cancer treatments. The aim of the thesis was to evaluate the potential of SPION to deliver localised hyperthermia by: (1) Characterization and comparison of SPION to select a lead candidate for clinical application. (2) Developing conjugation methods to confer SPION with cancer-binding properties by attachment of single chain Fv antibodies (scFv). (3) Evaluating the localisation and heating potential in vivo. SPION were characterized with regard to their hydrodynamic diameter, core size, magnetic properties, atomic iron content and heating potential for hyperthermia application. Different chemistries were evaluated to functionalize the most promising candidate using shMFEm, an scFv targeting the carcinoembryonic antigen (CEA). A CEA-non-binding scFv variant, shNFEm, was used as a negative control. Functionality of the scFv-SPIONs was assessed using quartz crystal microbalance. In vivo heating potential of the SPION was tested in a xenograft tumour model in vivo, using bespoke MACH apparatus. The results established Ferucarbotran (FX), unformulated Resovist®, an MRI contrast agent, as the most suitable candidate for hyperthermia application. Cyanogen bromide chemistry was selected to functionalise Ferucarbotran with the scFvs shMFEm. The FX-scFv conjugates were purified and analysed. Functionality was confirmed by quartz crystal microbalance, enabling the first visualisation of the interaction between a SPION-scFv conjugate and cognate antigen in real-time. The in vivo assessment of Ferucarbotran and the FX-scFv conjugates confirmed the in vitro heating potential of Ferucarbotran. In vivo analysis of heating showed that localised hyperthermia was achievable with intratumoral injection followed by MACH. Histological analysis of the tumours revealed an uneven distribution of particles within the tumours and an accumulation of the particles within the surrounding stroma indicating the future work should include study of innovative tumour delivery methods. These results support the hypothesis of a therapeutic potential for targeted magnetic nanoparticle hyperthermia and indicates the challenges that have be addressed to enable clinical application of this treatment modality.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.626455  DOI: Not available
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