Engineering Multi-functional Nanomaterials to Treat Metastatic Cancer

Prostate cancer is the most common type of cancer and the second most common cause of death in men in the UK. Cancer metastasis (cancer cells spread outside the primary tumour) is the most serious complication of prostate cancer, with median patient survival of 12-18 months with current available chemotherapeutics. Chemotherapy is an approach which utilises anti-cancer drugs for killing tumour cells however it is associated with undesirable side effects due to its acting on normal healthy cells. Following systemic administration, cytotoxic drugs are eliminated rapidly from the blood stream which results in poor drug accumulation at metastatic cancer lesions. To overcome these shortcomings, drugs have been encapsulated into ultra-small objects called "nanocarriers". Liposomes are one example of these nanocarriers, made of natural lipid composition thus considered as the safest nanocarrier systems developed so far. Encapsulation of drugs into liposomes prolongs their residency time in the blood by decreasing their renal and hepatic clearance. In addition, drug-loaded nanocarriers will utilise the tumour leaky vasculature, known as enhanced permeation and retention (EPR) effect, to improve drug delivery to cancer cells. However, the poor release of the drug from such nanocarriers is considered the main challenge in cancer drug delivery. In this proposal we describe the development of targeted delivery systems that recognise prostate cancer cells, and efficiently release the encapsulated chemotherapeutics in response to an externally applied magnetic field. Such an approach aims to increase drug accumulation at the tumour tissues, and reduce undesirable systemic side effects. The targeting ligand was chosen to recognise only prostate cancer cells as this targeting moiety recognises specific proteins (called PSMA) only expressed on this cell type thus sparing healthy tissues. To overcome the poor release of the drug, temperature-sensitive liposomes (TSL) will be formulated so that they "break down" and release the drug only at temperatures higher than the body temperature (i.e.42C). The temperature-sensitive liposomes will be developed by incorporating magnetic iron oxide nanoparticles inside the liposomes besides the anticancer drug. The magnetic nanoparticles will heat when exposed to a "safe" alternating magnetic field so that the drug can be released from the TSL. At the same time the magnetic nanoparticles will act as "imaging agents" so their accumulation in the tumour will be visualized by Magnetic Resonance Imaging (MRI). This proposal aims to translate our innovative delivery system as a potential therapy for metastatic prostate cancer. It is anticipated that safer and more effective targeted nanocarriers will emerge to treat metastatic prostate cancer so that chemotherapy side effects are hugely reduced.

This project will have an impact in academia and industry and will address all those interested in nanomedicine, in particular for cancer therapy. Such a collaborative project promises to bring about a long-term benefit to the development of UK science and its clinical translation. It is relevant to pharmaceutical and medical companies interested in developing novel therapeutic approaches to treat cancer (specifically metastatic cancers). The research aims to improve and expand on prostate cancer therapy options to prolong patient survival, and enhance the quality of life for UK and European citizens. It has the potential to contribute to knowledge transfer among the different national collaborators who are experts in their field. The development of nanopharmaceuticals is an emerging multidisciplinary area and research within a multidisciplinary team is mandatory for progress in the field. It is expected that a number of additional national, EU or independently funded collaborative projects will follow the developments achieved by this project. After showing a proof-of-concept how our multifunctional nanoparticles can be used to target and treat metastatic prostate cancer, future funding for further clinical testing and commercialisation of the novel temperature-sensitive nanoparticle-liposome hybrids will be sought along with an industrial partner.