Abstract
SummaryLately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.
Highlights
Tumor targeting by liposomes has been considered a promise for quite a few decades and can increase the therapeutic index [1, 2]
Drug targeting to tumors by liposomes has been assumed to depend on the enhanced permeation and retention (EPR) effect [2,3,4]: due to their specific size the liposomes should not extravasate into healthy tissues and should avoid renal clearance, whereas wide fenestrations in the leaky tumor vasculature would allow the liposomes to permeate into the tumor tissue
The results provide quantitative data of the pharmacokinetics of liposomal targeted drug delivery and demonstrate the quantitative availability of the released drug in different tissues
Summary
Tumor targeting by liposomes has been considered a promise for quite a few decades and can increase the therapeutic index [1, 2]. The absence of well-functioning lymphatic drainage in the tumor should result in enhanced tumor retention. In this respect, a stealth coat of hydrophilic polymers like polyethylene glycol (PEG) is important to delay the Invest New Drugs (2019) 37:890–901 uptake by the phagocytes of the mononuclear phagocyte system (MPS) and to attain a blood circulation time long enough for the nanoparticles to reach the tumor tissue. The success of tumor targeted delivery by nanomedicines including liposomes and the corresponding EPR effect has been questioned [4,5,6]. The availability of the released drug and the corresponding fate (i.e. retention, distribution, elimination) are as least as important as the behavior of the liposomal carrier
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