Pharmacokinetics and tissue disposition in monkeys of an antisense oligonucleotide inhibitor of Ha-ras encapsulated in stealth liposomes

Purpose. This study examined the pharmacokinetics and tissue distribution o f an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). Methods. Encapsulated or unencapsulated ISIS 2503 was administered to rhesu s monkeys by intravenous infusion. The concentrations of ISIS 2503 and meta bolites in blood, plasma, and tissue samples were determined by capillary g el electrophoresis. Results. Plasma concentrations of encapsulated ISIS 2503 decreased mono-exp onentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated I SIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distribute d primarily to the reticulo-endothelial system and there were few metabolit es observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to t issue with highest concentration seen in kidney and liver. Nuclease-mediate d metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. Conclusions. The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of c learance from the systemic circulation. These attributes may make these for mulations attractive for delivering oligonucleotides to sites with increase d vasculature permeability such as tumors or sites of inflammation.