The development of novel bioanalytical pipelines for the evaluation of Karyopherin silencing drug delivery systems

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OverviewCancer is associated with aberrant receptor signalling and cellular trafficking pathways to promote survival and growth of tumours. Karyopherin dysregulation, including aberrant overexpression contributes to resistance to chemotherapy and poor cancer prognosis. Recently, we used bioinformatics analysis from existing breast cancer clinical datasets to show that alterations in Karyopherin alpha-2 (KPNA2) expression can result in poor prognostic outcomes for patients with breast cancer across multiple breast cancer sub-phenotypes. Moreover, our recent in vitro analyses in a panel of triple-negative breast cancer cell lines indicate that KPNA2 plays a significant role in cellular metabolism and DNA repair ability, the targeting of which can be exploited to achieve cancer cell death. This project will consider the design of lipid nanoparticle based systems targeting karyopherins, and study their bioanalytical properties. The cellular interactions and uptake of these delivery systems will be considered in vitro.Aims and ObjectivesThis project aims to design new drug delivery systems based on gene editing that will disrupt karyopherin activity. These delivery systems and the process used for their design will be explored as a novel cancer treatment strategy for breast cancer. To deliver on this project aim, the objectives will include the (i) design and manufacture of new prototype particles, (ii) their comprehensive bioanalytical evaluation, and (iii) evaluation of their biological activity. We will examine manufacture process parameters and their impact on nanoparticle physicochemical properties and their cellular fate. Developing a deeper understanding of manufacture process parameters and impact on product performance is key to improving the clinical and commercial translation of new drug delivery technologies.