Pharmacokinetics and tissue disposition in monkeys of an antisense oligonucleotide inhibitor of Ha-ras encapsulated in stealth liposomes.
OBJECTIVE
This study examined the pharmacokinetics and tissue distribution of 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 rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis.


RESULTS
Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially 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 ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated 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 clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.
Yu
R Z
RZ
Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA. ryu@isisph.com
Geary
R S
RS
Leeds
J M
JM
Watanabe
T
T
Fitchett
J R
JR
Matson
J E
JE
Mehta
R
R
Hardee
G R
GR
Templin
M V
MV
Huang
K
K
Newman
M S
MS
Quinn
Y
Y
Uster
P
P
Zhu
G
G
Working
P K
PK
Horner
M
M
Nelson
J
J
Levin
A A
AA
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002214:Capsules / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006207:Half-Life; D007700:Kinetics; D008081:Liposomes; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D054735:Phosphorothioate Oligonucleotides; D014018:Tissue Distribution; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
D001798:Blood Proteins; D002214:Capsules; C122000:ISIS 2503; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D018631:ras Proteins