ABSTRACT
The key issue in targeted drug delivery is selectively enhancing drug accumulation at target sites. The usefulness of long-circulating particles within the nanoscale size range (‘‘stealth’’ particles) to this favorable property has been extensively documented (as, for example, in the relevant chapters in this book series). From a clinical application perspective, formulations of polyethylene glycol (PEG)-coated liposomes represent the prime example of such particles. These stealth liposomes circulate in the blood for prolonged periods of time, with reported half-lives up to 24 hours in mice and rats and about two days in humans. This enables significant localization in tumors and other pathological tissues with increased vascular permeability (1-4). Several formulations based on these long-circulating PEG-liposomes are commercially available
and/or in clinical testing (2,4). Despite this maturity, there are several clinically important issues not yet addressed sufficiently. In the clinical setting, the lipid dose needed depends on the intended application. Also, multiple dosing is often required. Remarkably, until recently, the effects of lipid dose and repeated administration on the pharmacokinetics of (empty) stealth liposomes have been largely neglected. Though in several studies the pharmacokinetics of liposomal cytostatics upon repeated administration were investigated, these studies focused on the fate of the drug rather than the carrier (2). This chapter summarizes the evidence obtained recently in our group and other laboratories showing that the long circulation property of PEG-liposomes is certainly not guaranteed under all circumstances.
