Metastatic disease is the major cause of cancer-related death in patients with solid tumours such as breast cancer. The mainstay of current treatments for metastatic disease is chemotherapy (e.g. doxorubicin) that is often limited by systemic toxicity. To improve drug efficacy, there is an urgent need for a mechanism to target tumour cells with minimal damage to normal tissues. Preliminary data shows that the Unfolded Protein Response (UPR) chaperone glucose-regulated protein 78 (GRP78) is overexpressed on the cell surface of multiple metastatic breast tumour tissues including spine, lung and heart (1). Targeting GRP78 on the surface of metastatic cancer cells with a GRP78 binding peptide fused to an apoptopic moiety exhibited promising effects in in vivo models of metastatic breast cancer (1) and a phase I trial of an IgM antibody targeting GRP78 (PAT-SM6) in subjects with relapsed or refractory multiple myeloma (NCT01727778) was recently completed. We have demonstrated previously that nanoparticles (NPs) can be targeted to colorectal cancer cells (2) and doxorubicin-loaded NPs exhibited similar toxicity to treatment with doxorubicin alone in in vitro studies with SY5Y neuroblastoma cancer cells (3).
The aim of my project is to develop and test a tumour specific drug delivery system using NPs that selectively target metastatic tumour cells by virtue of their high levels of surface-localised GRP78. The project will comprise the design, generation and characterization of a library of nanoparticles with optimal size and binding affinities for selective uptake by tumour cells and for optimal drug releasing properties within cells. Furthermore, selectivity towards tumour cells of GRP78 targeting NPs containing doxorubicin and the mode of internalisation and release of the doxorubicin will be tested. Having determined the biodistribution, toxicity and half-life of GRP78 targeting NPs, the efficacy in preclinical models of metastatic cancer, using either doxorubicin or an antagomir against microRNA-21 as the therapeutic agent, will be analysed.