INFLUENCE OF DOSE ON LIPOSOME CLEARANCE - CRITICAL ROLE OF BLOOD PROTEINS

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.