Title : Driving endocytosis for enhancing cellular delivery and intracellular targeting of therapeutics
Targeting disease processes inside cells with biopharmaceuticals represents a major challenge, not least in overcoming biological barriers such as those posed by the plasma membrane. Investment in this approach is justified when one considers the number individual intracellular targets now available to us as we continue to understand disease processes at the gene and protein level. This is true for many high-burden diseases including cancer, infectious diseases and inherited genetic defects such as cystic fibrosis. Our research at Cardiff University is focused on studying endocytosis and specifically on designing methods to analyse individual endocytic pathways to characterise how drug delivery vectors and associated therapeutics gain access to cells. As vectors we have paid particular attention to natural ligands, cell penetrating peptides and antibodies. We have focused on their capacity to not only interact with, and enter cells, but also on monitoring their intracellular traffic to reach a final destination. In this lecture I will describe work we have performed focusing on approaches we have used to study cell binding and endocytosis of drug delivery vectors including cell penetrating peptides, ligand decorated nanoparticles and antibodies targeting plasma membrane receptors on cancer cells. I will highlight how Internalisation of receptors can be significantly enhanced through manipulating ligand and receptor association, and how normal endocytic routes can be modified to reach a desired intracellular location. Our involvement in a €30M FP7 Innovative Medicine Initiative (IMI-EFPIA) consortium (COMPACT www.compact-research.org/) will also be discussed. This represents a public-private collaboration between 14 European academic institutes and pharmaceutical companies aiming to improve the cellular delivery of biopharmaceuticals across major biological barriers of the intestine, lung, blood brain barrier and skin.
•That effective plasma membrane targeting is not always associated with effective internalisation to reach the intracellular target.
•That there is a need for more basic research and understanding of natural mechanisms governing endocytosis of plasma membrane receptors that are selected for therapeutic targeting. Then new drug delivery formulations can be designed to better promote cellular uptake of targeted receptors and modify intracellular targeting to provide the therapeutic cargo with a better chance of reaching its target.
•That ligand valency on nanoparticles designed as drug delivery vectors is critical for not only targeting at the plasma membrane but also in directing endocytic traffic to different subcellular compartments.