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 that is often limited by systemic toxicity. To improve drug efficacy, there is a need for a mechanism to target tumour cells with minimal damage to normal tissues. Preliminary data show 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 apoptotic moiety showed promising effects in in vivo models of metastatic breast cancer.1 We have demonstrated previously that nanoparticles (NPs) can be targeted to colorectal cancer cells2 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 NPs with optimal size and binding affinities for selective uptake by tumour cells and for optimal drug releasing properties within cells. 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 therapeutic agent, will be analysed.
To date, a library of multiple NPs of different sizes and containing different lengths of polyethylene glycol (PEG) side chains has been generated and chemically characterized. NPs were loaded with Cyanine5 (Cy5) to analyse their cancer cell attachment properties. PEGylated NPs linked to a GRP78 binding peptide showed stronger tumour cell association with surface GRP78-positive 4T1.2 cells than NPs linked to a scrambled peptide or a PEG side chain.