Lung cancer stands as one of the deadliest diseases, responsible for the most cancer related deaths worldwide. The UK 5-year survival rate of non-small-cell lung cancer (NSCLC), the predominant subtype of lung cancer, stands at 9.5%, highlighting an unmet need for therapeutic intervention. A key issue is the lack of efficacy current chemotherapy regimens have in the clinic. These therapies often suffer from poor tumour targeting, resulting in dissemination throughout the body and inadequate concentrations in the tumour. This causes deleterious side effects contributing to a reduced patient quality of life and ultimately survival.
Nanomedicine may serve to overcome the current therapeutic hurdles in treating NSCLC; the use of nanoparticles (NPs) for the delivery of drugs can improve drug targeting to tumours, increasing efficacy and attenuating off-target side effects. NPs can be used to deliver multiple drugs and be made from varying materials such as gold (AuNPs) or polymers. Furthermore, the discovery of oncogenic mutations in genes like EGFR present druggable targets in patients harbouring the appropriate mutations. This can also be taken advantage of using NPs to more directly target tumours and increase therapeutic response. Therefore, the aim of this thesis was to develop novel NP formulations comprised of a chemically modified variant of the tyrosine kinase inhibitor afatinib and gold (Afb-AuNPs) or in combination with vinorelbine as a polymeric dual chemotherapy formulation (Dual-NPs).
Drug-bearing NPs were synthesised using a combination of organic chemistry and hydrophobic ion pairing, after which the NPs were extensively characterised to discern their physicochemical properties. We then sought to investigate the in vitro efficacy of NPs. Cell viability studies revealed Afb-AuNPs and Dual-NPs were significantly cytotoxic to various NSCLC cell lines and comparatively nontoxic to noncancerous cells. Moreover, NP formulations were found to significantly inhibit proliferation of A549, H226 and PC-9 cells
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compared to clinical formulations as determined by electric cell-substrate impedance sensing. The mechanism of uptake in cancer cells was elucidated using fluorescent NPs as a model system and quantified using confocal microscopy. Finally, the in vivo activity of biocompatibility of Dual-NPs was investigated in a physiologically relevant murine model of NSCLC. Taken together, these results highlight the therapeutic potential for NP formulations of chemotherapy.