THERMOSENSITIVE LIPOSOMES - EXTRAVASATION AND RELEASE OF CONTENTS IN TUMOR MICROVASCULAR NETWORKS

Purpose: The purpose of this study was to determine whether hypertherm ic exposure would accelerate drug release from thermosensitive sterica lly stabilized liposomes and enhance their extravasation in tumor tiss ues, Materials and Methods: In vivo fluorescence video microscopy was used to measure the extravasation of liposomes, as well as release of their contents, in a rat skin flap window chamber containing a vascula rized mammary adenocarcinoma under defined thermal conditions (34 degr ees, 42 degrees, and 45 degrees C), Images of tissue areas containing multiple blood vessels were recorded via a SIT camera immediately befo re, and for up to 2 h after i,v, injection of two liposome populations with identical lipid composition: one liposome preparation was surfac e labeled with Rhodamine-PE (Rh-PE) and the other contained either Dox orubicin (Dox) or calcein at self-quenching concentrations, The light intensity of the entire tissue area was measured at 34 degrees C (the physiological temperature of the skin) for 1 h, and at 42 degrees or 4 5 degrees C for a second hour, These measurements were then used to ca lculate the fluorescent light intensity arising from each tracer (lipo some surface label and the released contents) inside the vessel and in the interstitial region, Results: The calculated intensity of Rh-PE f or the thermosensitive liposomes in the interstitial space (which repr esents the amount of extravasated liposomes) was low during the first hour, while temperature was maintained at 34 degrees C and increased t o 47 times its level before heating, when the tumor was heated at 42 d egrees or 45 degrees C for 1 h, The calculated intensity of the liposo me contents (Dox) in the interstitial space was negligible at 34 degre es C, and increased by 38- and 76-fold, when the tumor was heated at 4 2 degrees and 45 degrees C for 1 h, respectively, Similar values were obtained when calcein was encapsulated in liposomes instead of Dox, A similar increase in liposome extravasation was seen with nonthermosens itive liposomes, but negligible release of Dox occurred when the windo w chamber was heated to 45 degrees C for 1 h, Extravasation of liposom es continued after heating was stopped, but content release stopped af ter removal of heat, Release of Dox from extravasated liposomes was al so seen if heating was applied 24 h after liposome administration, but no further enhancement of liposome extravasation occurred in this cas e, Conclusions: Our data suggest that hyperthermia can be used to sele ctively enhance both the delivery and the rate of release of drugs fro m thermosensitive Liposomes to targeted tissues. Copyright (C) 1996 El sevier Science Inc.