Stabilized plasmid-lipid particles: Pharmacokinetics and plasmid delivery to distal tumors following intravenous injection

A previous study has shown that plasmid DNA can be encapsulated in lipid particles (SPLP, stabilized plasmid lipid particles) of approximately 70 nm diameter composed of 1,2-dioleoyl-3-phosphatidyl-ethanolamine (DOPE), the cationic lipid N,N-dioleoyl-N,N-dimethylammonium chloride (DODAC) and poly(ethylene glycol) conjugated to ceramide (PEG-Cer) using a detergent dialysis process (Wheeler et al. (1999) Gene Therapy 6, 271-281). In this work we evaluated the potential of these SPLPs as systemic gene therapy vectors, determining their pharmacokinetics and the biodistribution of the plasmid and lipid components. It is shown that the brood clearance and the biodistribution of the SPLPs can be modulated by varying the acyl chain length of the ceramide group used as lipid anchor for the PEG polymer. Circulation lifetimes observed for SPLPs with PEG-CerC(14) and PEG-CerC(20) were t(1/2) = similar to 1 and similar to 10 h, respectively. The SPLPs are stable while circulating in the blood and the encapsulated DNA is fully protected from degradation by serum nucleases, The accelerated clearance of SPLPs with PEG-CerC(14) is accompanied by increased accumulation in liver and spleen as compared to PEG-CerC(20) SPLPs. Delivery of intact plasmid to liver and spleen was detected. Significant accumulation (approximately 10% of injected dose) of the long circulating SPLPs with PEG-CerC(20) in a distal tumor (Lewis lung tumor in the mouse flank) was observed following iv application and delivery of intact plasmid to tumor tissue at approximately 6% injected dose/g tissue is demonstrated.