Accumulation of protein-coated liposomes in an extravascular site: influence of increasing carrier circulation lifetimes.
The primary objective of this work was to test whether increased blood levels and circulation lifetimes result in increased passive targeting of protein-coated liposomal drug carriers. The system used to evaluate this was based on i.v. injection of 100 nm of distearoyl phosphatidylcholine/cholesterol liposomes with covalently bound streptavidin. The circulation lifetime of these liposomes was increased by procedures that involved blockade of liposome uptake by phagocytic cells in the liver and/or the incorporation of a poly(ethylene glycol)-modified phospholipid [poly(ethylene glycol)2000-modified distearoyl phosphatidylethanolamine]. Blockade of liver phagocytic cells with a low predose (2 mg/kg of drug) of liposomal doxorubicin increased the circulation half-life of the streptavidin liposomes from less than 1 hr to greater than 3 hr. A further 2-fold increase in circulating half-life (to approximately 7.5 hr) was achieved by using liposomes with 2 mole % of poly(ethylene glycol)2000-modified phosphatidylethanolamine. In combination with RES blockade, the circulation lifetimes of poly(ethylene glycol)phosphatidylethanolamine containing streptavidin liposomes could be increased to greater than 12 hr. The ability of these liposomes to move from the plasma compartment to an extravascular compartment was measured by using the peritoneal cavity as a convenient, accessible, extravascular site. The tendency for liposomes to accumulate in this site was not, however, clearly dependent on circulating blood levels. Comparable levels of liposomes in the peritoneal cavity were achieved when using systems that exhibited significantly different circulation lifetimes.
British Columbia Cancer Agency, Vancouver, Canada.
S A
SA
Longman
P G
PG
Tardi
M J
MJ
Parr
L
L
Choi
P R
PR
Cullis
M B
MB
Bally
D000818:Animals; D001426:Bacterial Proteins / Q000493:pharmacokinetics; D004337:Drug Carriers; D005260:Female; D007941:Leukemia P388 / Q000473:pathology; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D051379:Mice; D012157:Mononuclear Phagocyte System / Q000187:drug effects; D010529:Peritoneal Cavity; D010743:Phospholipids / Q000737:chemistry; D011092:Polyethylene Glycols / Q000493:pharmacokinetics; D019809:Streptavidin; D014018:Tissue Distribution
D001426:Bacterial Proteins; D004337:Drug Carriers; D008081:Liposomes; D010743:Phospholipids; D011092:Polyethylene Glycols; D019809:Streptavidin