Development of long-circulating polyelectrolyte complexes for systemic delivery of genes

Extended systemic circulation of vectors for gene delivery has long been a goal for cancer gene therapy. In recent years, several groups have evaluated the feasibility of gaining extended circulation of polyplex vectors by endowing them with steric stabilisation, resulting from the presence of a surface layer of hydrophilic polymer. Although this approach has been in itself mainly unsuccessful, remarkable progress has been gained when steric stabilisation has been combined with "lateral stabilisation", using a range of agents to crosslink the surface of the complexes. Lateral stabilisation has been achieved using low molecular weight crosslinking agents, and also using multivalent polymers designed for cooperative surface attachment to the polyplex. In this way plasma clearance kinetics can be substantially extended, with alpha half lives for clearance in excess of 90 min. In order to enable transgene expression within target cells it can be necessary for the vectors to undergo triggered activation following arrival at the target site. The most promising way to achieve this is by reductive activation of the vector within the cytoplasm or nucleus of the target cell. State of the art in this rapidly progressing field is reviewed.