Highly Tunable Modular Dendrons for DNA Binding and Delivery

摘要

Over the last 20 years, intense interest has developed in the field of gene therapy – the use of genetic material such as DNA or siRNA to intervene in medically relevant biological pathways – but as yet, a practical approach for in vivo gene delivery has not been forthcoming. Much attention has focused on viral delivery, but unfortunately, when applied clinically, viruses have led to problems such as immune response or leukemia. As such, attention is increasingly focusing on synthetic delivery vehicles. Non-viral vectors are divided into two classes – cationic polymers4 and cationic lipids. Dendrimers are polymers with well-defined, branched nanoscale structures, and there has been considerable interest in the use of cationic dendrimers for gene delivery. After pioneering work with poly(amidoamine) (PAMAM) dendrimers, a wide range of dendrimers have been applied in gene delivery – including poly-L-lysine8 and poly(propylene imine) (PPI) derived systems. Unlike spherical dendrimers, dendrons have the shape of an individual branching unit, and as such, they can be functionalized both on their branched surface and at their focal point. This gives dendrons a high degree of synthetic tunability. Research from the groups of Florence and Diederich employed hydrophobically modified dendrons which behaved more like cationic lipids than like cationic polymers. This inspired our interest in the development of dendrons for DNA binding – a research program which has been running over the past five years in York. In particular, we wanted to demonstrate how all regions of the dendritic architecture could be tuned synthetically, and the impact of this on DNA binding and delivery. This contribution, for the first time, draws these ideas together, providing new insight and demonstrating the versatility of our highly tunable modular approach.