Peptide Prodrugs: Using Host Defence Peptides as Therapeutic Anticancer Agents

According to the World Health Organization (WHO), Cancer is the leading cause of death worldwide, accounting for around 13% of all deaths in the world annually. The design of cancer chemotherapy has become increasingly sophisticated and the treatment of cancer has become increasingly specific with concentration focused on molecular targets. At the moment, there is still no cancer treatment that is 100% efficient against wide spread cancer so there is still a growing demand for the investigation into developing novel anticancer agents. This project is aimed at developing prodrugs of Host defence peptides (HDPs). HDPs are multifunctional molecular effectors of innate immunity, the first line of defence against infection in multicellular organisms. Their synthetic derivatives also have exciting potential as anti cancer agents. In the development of the project, three different approaches were taken to explore some of the different targeting mechanisms of drug delivery; The first approach involves a dual release prodrug which contains a PEGylated HDP joined by a degradable enzyme peptide linker. On the other side of the PEG is a classical anticancer agent attached by an acid labile functional. These linkers are key to allow the release of the peptide and anticancer agent upon degradation or change in pH conditions, and are suitable for lysosomotropic delivery. The second approach is a peptide prodrug which exploits enzyme degradable linkers and allows for targeted delivery against various types of cancer cells. The third approach is a delivery technique using a HDP as a vector to deliver a pro apoptotic peptide sequence into the cancer cell, as well as an active anticancer agent, contributing to the overall activity of the dimer.