Size-dependent extravasation and interstitial localization of polyethyleneglycol liposomes in solid tumor-bearing mice

We have examined the size dependence of extravasation and interstitial loca lization of polyethyleneglycol-coated liposomes (PEG-liposomes) in the soli d tumor tissue by means of electron microscopic observation. Liposomes comp osed:of distearoyl phosphatidylcholine, cholesterol and distearoylphosphati dylethanolamine derivative of polyethyleneglycol (PEG) were prepared in var ious size ranges. PEG-liposomes with an average diameter of 100-200 nm show ed the most prolonged circulation lime and the greatest tumor accumulation in all the solid tumors employed in this experiment. Although large PEG-lip osomes with a diameter of 400 nm showed a short circulation time in normal mice, the results in splenectomized mice indicated that they do have an int rinsic prolonged circulation character in vivo. However, large PEG-liposome s could not extravasate into solid tumor tissue. These results indicate tha t-the size of liposomes is critical for extravasation. The electron microsc opic observations revealed the almost exclusive engulfment of extravasated liposomes by tumor-associated macrophages; very few were taken up by tumor cells. (C) 1999 Elsevier Science B.V. All rights reserved.