The development of a novel magnetic nanomedicine for the treatment of aggressive metastatic breast cancer

Background: Oncolytic virotherapy is a novel immunotherapy generating success in clinical studies in multiple cancer types. However, clinical use of oncolytic viruses (OVs) to date is limited to superficial tumours due to poor tumour penetration and viral elimination by the immune system following systemic delivery. A way to overcome this, is to use magnetic nanoparticles (MNPs) in combination with magnetic drug targeting. This customisability of MNPs allows for the stable conjugation of OVs and the controlled drug release of additional drug molecules. The aim of this PhD was to develop a magnetic nanomedicine (MNM) consisting of the OV (Herpes Simplex Virus1716 (HSV1716)) and a chemotherapy (epirubicin), bound to MNPs. We hypothesise that this will improve drug delivery into aggressive breast cancer (BC) cells using an external magnetic field. Methods: The intrinsic physical and chemical characteristics of the MNM were determined prior to pre-clinical analysis using XRD, FRIT, TEM, SQUID (as well as others). The oncolytic and pro-inflammatory potential of the MNM was investigated in vitro in a panel of BC cell lines using plaque assays, alamar blue and RT-PCR. The tolerability and antitumour efficacy of the MNM was assessed using pre-clinical models of primary and metastatic BC. Results: MNPs were successfully functionalised and biochemically conjugate to a pH sensitive epirubicin and HSV1716 resulting in a stable complex, even after freeze-thawing. Moreover, the MNM was as cytotoxic as the individual drugs in murine and human BC cell lines, and could potentially generate a pro-inflammatory response. All animals tolerated the MNM treatment regime with no adverse effects in both primary and metastatic models, with the MNM demonstrating the ability to cross the blood brain barrier following systemic delivery. Moreover, therapeutic efficacy was observed through reduced tumour burden and prolonged survival. Conclusion: In summary, we have developed a novel MNM which is effective in pre-clinical models of BC. Future studies will further seek to address the antitumour activity of the MNM, as well as its bio-distribution following treatment in vivo. Future consideration will need to be given to the MNM for production and scale up for clinical use.N