Cd. Oja et al., INFLUENCE OF DOSE ON LIPOSOME CLEARANCE - CRITICAL ROLE OF BLOOD PROTEINS, Biochimica et biophysica acta. Biomembranes, 1281(1), 1996, pp. 31-37
It is well established that the circulation half-life of liposomes inc
reases with increasing dose. This effect is commonly attributed to 'sa
turation' of the fixed and free macrophages of the reticuloendothelial
system resulting in reduced clearance rates. However, it is also know
n that the clearance rate of liposomes is dependent on the amount of a
ssociated blood protein, leading to the possibility that dose-dependen
t increases in circulation lifetimes could be due to decreases in the
amount of blood protein associated per liposome. In order to test this
hypothesis, the protein binding and clearance properties of large uni
lamellar liposomes composed of distearoylphosphatidylcholine/cholester
ol and egg phosphatidylcholine/dioleoylphosphatidic acid/cholesterol w
ere examined in mice. Liposomes were injected over a dose range of 10
to 1000 mg lipid/kg body weight, and the circulation lifetime and live
r and spleen accumulation monitored. As expected, longer circulation h
alf-lives were observed at higher doses for both liposome compositions
. However, it was also found that at higher liposome doses, significan
tly less protein was bound per liposome. The results indicate that the
re is a limited pool of blood proteins that is able to interact with l
iposomes of a given composition. At higher lipid doses these blood pro
teins are distributed over more liposomes resulting in lower protein b
inding values and longer circulation lifetimes.