The phospholipid component of small unilamellar liposomes controls the rate of clearance of entrapped solutes from the circulation

Abstract

Successful use of liposomes as a drug carrier in vivo is often dependent on their prolonged presence in the blood [ 1,2]. This is expected to reduce uptake of liposomes by the reticuloendothelial system and allow them to deliver drugs to alternative cell targets [ 11. To this end, there has been modest success through the manipulation of liposomal surface charge [3] and size [4]. However, with liposomes that have little or no cholesterol, entrapped solutes leak out rapidly in the presence of blood. Solute leakage is effected through the loss of phospholipid molecules to plasma high density lipoproteins and ensuing bilayer destabilization [5-71. We have found that the presence of excess cholesterol in the bilayers greatly diminishes such phospholipid movement, thereby preserving their stability [7-91. Thus, solutes carried by neutral or positively charged small unilamellar cholesterol-rich liposomes composed of egg phosphatidylcholine can attain a half-life in rodents (-2 h) which is similar to that exhibited by the carrier [4,7]. Here, we have investigated conditions that will allow circulating liposomes to extend their presence in the blood considerably and at the same time enable them to retain solutes quantitatively. Our data show that, for small unilamellar neutral liposomes, the halflife of their solute content in the circulation of mice can be controlled by the appropriate choice of the phospholipid component and the addition of excess cholesterol or its omission. Extended half-life (<16 h) of the solute is reflected in its reduced uptake by the liver and spleen.