EFFECTS OF THE SIZE AND FLUIDITY OF LIPOSOMES ON THEIR ACCUMULATION IN TUMORS - A PRESUMPTION OF THEIR INTERACTION WITH TUMORS

The distribution of liposomes with different membrane fluidity and ves icle size in tumors after intravenous injection was investigated in Yo shida sarcoma-bearing rats. Liposomes composed of egg phosphatidylchol ine (EPC) or hydrogenated egg phosphatidylcholine (HEPC), dicetyl phos phate and cholesterol in a molar ratio of 5:1:4 were prepared. Their s ize was adjusted so that they had various mean diameters, ranging from 40 to 400 nm. In EPC liposomes, whose membranes were more fluid than those of HEPC liposomes, tumor accumulation increased with increasing area under the blood concentration-time curve (AUG). The size of lipos omes which showed the greatest tumor accumulation and AUC was around 1 00 nm in diameter. In HEPC liposomes, the less fluid type, the size de pendence of tumor accumulation and AUC differed. The greatest tumor ac cumulation or AUC were found in liposomes with a diameter of about 100 or 40 nm, respectively. This discrepancy indicates that the tumor acc umulation of liposomes is not always correlated with their circulation time in the blood. To clarify the process by which these liposomes ac cumulate from the vascular space into the tumor, we calculated tumor u ptake clearance (CL(tu)), which can separate the contribution of the b lood concentration from the accumulation in tumor. The CL(tu) values f or EPC and HEPC liposomes agreed at all sizes, liposomes with a diamet er of 100 nm showing the highest values. These findings indicate that the accumulation of liposomes from the vascular space into the tumor i s primarily governed by their size and not by their membrane fluidity or blood circulation time. When tumor blood flow was selectively enhan ced by the infusion of angiotensin II, the CL(tu) of 100-nm liposomes decreased to the level of that in 40-nm liposomes, suggesting that som e histological factor(s) in the tumor may be responsible for the local ization of 100-nm liposomes in tumor. In an in vitro experiment using cultured Yoshida sarcoma cells, 59-nm HEPC liposomes were directly tak en up by the tumor cells to an extent at least 2.5-times greater than larger liposomes (greater than or equal to 100 nm). We conclude that 1 00-nm liposomes may predominantly localize in the interstitial space, whereas some liposomes of smaller size may be taken up by tumor cells.