| Summary: | This thesis concerns the interactions experienced by liposomal drug delivery systems as
they circulate in the blood and their influence on elimination behaviour. These studies are divided
into three areas, which investigate three factors influencing liposome elimination behaviour - lipid
dose, poly(ethylene glycol) (PEG)-polymer coating and the generation of an immune response
to liposome systems.
First, the influence of lipid dose on elimination has previously been attributed to
'saturation' of the free and fixed macrophages of the reticuloendothelial system (RES) at high
lipid doses. Here the potential role of blood protein binding by liposomes is examined. Protein
binding and elimination properties of two representative compositions of large unilamellar
vesicles were examined in mice over a dose range of 10-1000 mg lipid / kg body weight.
Although longer half-lives were observed for higher doses even the highest lipid doses of the
most rapidly cleared liposome compositions failed to completely saturate RES uptake. However,
these higher dose liposomes did bind significantly less protein as measured on a protein-to-lipid
basis. These results suggest the existence of a specific pool of blood proteins that interacts with
liposomes of a given composition, and is diluted over larger surface areas at higher lipid doses,
resulting in less efficient protein-mediated RES uptake.
A second method of influencing liposome elimination behaviour is through "steric
stabilization" of liposomes by incorporation of PEG polymer coatings. This enhances circulation
lifetimes and increases delivery of drugs to sites of disease. It has been conjectured that reduction
of blood protein adsorption to liposomes is the primary mechanism leading to longer circulation lifetimes of these systems, however this remains to be confirmed in vivo. These studies employed
three representative lipid compositions to demonstrate that incorporation of PEG induces a
nonspecific reduction of blood protein bound to vesicles in the circulation of mice. This reduced
blood protein adsorption correlated with the increased circulation lifetimes of the vesicles. Dosedependent
changes in circulation lifetime, similar to those observed for conventional lipid
compositions, were noted.
A third factor which can dramatically alter liposome elimination behaviour is the
generation of immune responses - particularly against the surface-coupled antibodies or ligands
of targeted liposomes. This results in rapid elimination of subsequent administrations, therefore
limiting potential applications. Liposomes are known to interact with cells responsible for antigen
processing and presentation, antibody production and cell-mediated immunity. Therefore, it was
investigated whether the toxic effects of encapsulated drugs on cells of the immune system could
solve this problem. Liposome elimination and humoral immune response were monitored for
repeated administrations of doxorubicin encapsulated in liposomes with ovalbumin covalently
coupled to the surface. The results showed that, at high drug-to-lipid ratios low doses of
encapsulated doxorubicin prevented humoral immunity against repeated administration of
ovalbumin-proteoliposomes. Immunosuppression was specific for the ovalbumin bound to drugloaded
vesicles at low drug doses. This suggests a selective suppression of immunity against the
target ligand for low doses of doxorubicin-loaded targeted liposomes which could prove
advantageous for safe repeated administration. === Medicine, Faculty of === Biochemistry and Molecular Biology, Department of === Graduate
|
|---|
