Long-circulating vectors for the systemic delivery of genes

The development of vectors capable of treating systemic diseases is an important goal for gene therapy protocols. In order for a carrier system to preferentially accumulate at sites of systemic disease, such as tumors, sites of inflammation and sites of infection, the carrier must exhibit long circulation lifetimes following intravenous injection. Unfortunately, most gene delivery systems, including viral vectors as well as non-viral vectors, e.g., lipoplexes, polyplexes and lipopolyplexes, are rapidly cleared from the circulation and are preferentially taken up by the 'first-pass' organs such as liver, lung and spleen. Here we review recent literature concerning the ability of non-viral vectors to act as systemic gene therapy agents. The most promising systemic vectors are liposomal systems in which plasmid DNA is encapsulated within a lipid bilayer. The stabilized plasmid-lipid particle (SPLP) system, for example, exhibits circulation half-lives of the order of 6 h following intravenous injection, and preferentially accumulates in distal tumors with gene expression primarily localized to the tumor site.