Cell-targeting peptides for selective drug delivery to tumour cells

Abstract

Cancer stands out as a disease that could benefit immensely from targeted drug delivery. The presence of molecular biomarkers that differentiate cancer cells from their surrounding cells is an often overlooked opportunity for developing a smart therapy with the ability to selectively target and terminate cells. Despite the increasing knowledge of cellular makeup, ligand identification remains a major setback in the development of effective and selective chemotherapies. The overall aim of this Thesis is to devise drug delivery systems suitable for harnessing the bioactivity of phage-derived cell-targeting peptides as a potential targeted treatment modality. This principal objective was explored by first producing a cell-targeting peptide for constructing a monomeric peptide-drug conjugate system, which was then used as a targeting ligand for a polymersome nanoparticle system. The successful synthesis of the cell-targeting peptide-drug conjugate using a phage-derived E1-3 peptide was followed by a series of in vitro studies performed to understand the viability of the phage-derived peptide as a drug carrier. These in vitro experiments revealed that the cell-targeting peptide derived from phage display screening could be conjugated to an anticancer drug without compromising its affinity to target cells. Furthermore, addition of this peptide resulted in an effective enhancement in drug selectivity towards its target medulloblastoma cells, DAOY. The promising outcomes from this system were extended to a nanoparticle system where the peptide moiety was incorporated onto the backbone of a diblock terpolymer. Self-assembly of this polymer produced polymersomes with a unique ellipsoidal shape. The advantage of this system was its tuneable properties, providing an excellent model for studying the effect of particle sizes, ligand density, and multivalency on nano-bio interactions. Subsequent biological evaluations of these polymersomes demonstrated the cell-targeting capability of these peptide-functionalised polymersomes towards its target. Preliminary testing on another sonic hedgehog medulloblastoma cell lines, UW228 also suggested the potential use of this system for targeting other cells in the same disease subgroup. The work described herein addresses some of the challenges and opportunities of cell-targeting peptides in the design of targeted drug delivery vehicles, which ultimately contribute to the rational design of targeted therapy.