Investigation into Synthetic Biodegradable Polymers for Delivery of Novel Drug Payloads to the Cell Interior

There is a need to better understand the mechanisms of entry into the cell cytoplasm and nucleus in order to design optimal delivery systems for biological molecules. On the one hand, this would open up significant opportunities to deliver potent drug payloads against intracellular targets to positively impact human health. In addition the project aims to develop a more general understanding of the rules governing the uptake of biological molecules into cells. This would benefit areas of basic research, for example in helping others to develop better imaging tools to explore intracellular biology in live cells and even in whole organisms. Viruses, although every efficient at intracellular delivery, have safety implications due to a possible risk of integration into the genome. This project proposes to investigate the use of synthetic, biodegradable polymers for delivery of a variety of drug payloads into the cell cytoplasm and nucleus. The novel pH-responsive polymeric nanoparticles have been designed to mimic the activity of viruses, both in their cell entry and endosomal escape mechanisms. Using cancer cell lines as a model system, the aim is to test out a variety of different biological payload formats for their ability to enter the cell and trigger apoptosis and subsequently cell death. Using conjugation and complexation approaches, the polymer would be tested with siRNA, antisense, peptide and antibody mimetic payloads in a quantitative comparison of cell killing efficiency. With an efficient model system established, there would then be scope to optimise and study the system in terms of the kinetics and mechanisms of cell entry, cytoplasmic and nuclear localisation, and the biodegradation of the polymers. There would also be scope to explore the efficiency in other cell systems and with further intracellular targets.