Weng-Jiang, Xian; (2017) Aqueous in-flow synthesis of T1 enhancing iron oxide nanoparticles for breast cancer theranostics. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) have gained signif- icant interest over the past decades because of their wide range of appli- cations. In biomedicine, SPIONs had been used extensively in the past as MRI contrast agents but they are currently being investigated for hyperther- mia therapies, magnetic manipulation and as part of diagnostic devices. The main aim of this study is to develop a method to synthesise positive MRI enhancing iron oxide nanoparticles (T1) and use these as the diagnos- tic component to produce a theranostic (therapeutic and diagnostic) agent. An aqueous flow-based synthesis method was assembled and tested producing 25nm iron oxide nanoparticles with T1 enhancement, CMDxUS- PIONs. The devised synthetic method enabled the fabrication of the desired nanoparticles without the use of organic solvents and at higher outputs than previously reported with flow-based methods, with 12 clinical doses being produced per hour using a lab-scale system. Surface functionalisation of CMDxUSPIONs with aptamers for active targeting was accomplished using a recently discovered anti-annexin 2A aptamer (ACE4). Particle uptake results show that ACE4-CMDxUSPIONs presented at least a two-fold increase in cell uptake when compared to un- modified CMDxUSPIONs. Further modifications of CMDxUSPIONs included drug-loading with cisplatin. Cisplatin loaded CMDxUSPIONs (CPt-CMDxUSPIONs) were achieved following pre-optimisation using a Design of Experiments ap- proach. The drug-loaded CPt-CMDxUSPIONs containing 0.64mg of CPt/mg of iron were able to retain both the activity of free cisplatin (in vitro) and the imaging capabilities of CMDxUSPIONs. In vivo experiments using a 4T1 mammary carcinoma cell line in Balb/C mice showed that CPt-CMDxUSPIONs were trackable in a 1T preclinical MRI and therapeutically, CPt-CMDxUSPIONs reduced tumour size and minimised cisplatin’s nephro- toxicity. Moreover, preclinical MRI scans show that it is possible to use CMDxUSPIONs as reporters for nanoparticle uptake detected by a T1-T2 signal switch in MRI. Iron oxide based theranostic systems reported in this thesis could play an important role in future cancer treatments by enabling a personalised therapy approach and modifying current chemotherapeutic drug biodistribu- tion as a carrier. The facile synthesis together with the addition of therapeu- tic agents to iron oxide nanoparticles demonstrates that the production of an experimental theranostic is possible.

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