Opponent: Professor Arwyn T. Jones, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales

Abstract

Oligonucleotide-based drugs hold great promise for the treatment of many types of diseases, ranging from genetic disorders to viral infections and cancer. However, efficient delivery across the cell membrane is a requirement for oligonucleotides to have an effect. Cell-penetrating peptides (CPPs) provide a solution to this problem. CPPs are capable of transporting cargoes such as drugs or nucleic acids for gene therapy into the cell, either by covalent conjugation to the cargo or by non-covalent complex formation. This thesis is focused on the development of a class of peptides called PepFects, peptides with fatty acid modifications and endosomolytic properties capable of forming nanoparticle-sized complexes with oligonucleotides. These complexes are efficiently taken up in many different cell types and are generally non-toxic and non-immunogenic.

We have developed a number of novel PepFect peptides and a quantitative structure-activity model to predict the biological effect of our peptides. In addition, we have studied the involvement of scavenger receptors class A in the endocytic uptake of PepFect complexes as well as other CPPs and polymeric transfection agents. Lastly, we have developed a series of PepFect peptides for delivery across the blood-brain barrier and a model system mimicking the blood-brain barrier in order to evaluate the passage of these peptides.

The general aim of this thesis is to improve the understanding of intracellular delivery using PepFect peptides from both a chemical and a biological viewpoint, and further improve the efficacy of this delivery system with the long-term goal of making it useful in clinical settings