Stabilized plasmid-lipid particles for systemic gene therapy

The structure of 'stabilized plasmid-lipid particles' (SPLP) and their prop erties as systemic gene therapy vectors has been investigated. We show that SPLP can be visualized employing cryo-electron microscopy to be homogeneou s particles of diameter 72 +/- 5 nm consisting of a lipid bilayer surroundi ng a core of plasmid DNA. It is also shown that SPLP exhibit long circulati on lifetimes (circulation half-life >6 h) following intravenous (i.v.) inje ction in a murine tumor model resulting in accumulation of up to 3% of the total injected dose and concomitant reporter gene expression at a distal (h ind flank) tumor site. In contrast, i.v. injection of naked plasmid DNA or plasmid DNA-cationic liposome complexes did not result in significant plasm id delivery to the tumor site or gene expression at that site. Furthermore, it is shown that high doses of SPLP corresponding to 175 mug plasmid per m ouse are nontoxic as assayed by monitoring serum enzyme levels, whereas i.v . injection of complexes give rise to significant toxicity at dose levels a bove 20 mug plasmid per mouse. It is concluded that SPLP exhibit properties consistent with potential utility as a nontoxic systemic gene therapy vect or.