MASSAGE-INDUCED RELEASE OF SUBCUTANEOUSLY INJECTED LIPOSOME-ENCAPSULATED DRUGS TO THE BLOOD

Liposome-based, externally regulated drug delivery system is described in which liposome-encapsulated bioactive molecules can be delivered i nto the blood in response to simple mechanical action. Without any mec hanical stimulation, subcutaneously injected 200 nm liposomes are usua lly trapped in the interstitial space for prolonged time. However, upo n lymphotropic stimulation (such as manual massage of the injection si te), the liposomes can be mobilized into the blood via lymphatic pathw ay. Up to 40% of the injected dose can be delivered to the blood via l ymphatic pathway from the injection site at the rabbit's front paw dor sum during 5 min manual massage cycle. Using vasoconstricting hormone angiotensin II as liposome-encapsulated pharmacological marker, we dem onstrated that physiological response to encapsulated drug (average bl ood pressure increase) can also be induced and modulated by massage. M assage itself was found to have no effect on the blood pressure. Modif ication of liposome surface with polyethylene glycol was found to incr ease blood localization of the liposome-encapsulated drug presumably d ue to decreasing the uptake of the drug carrier by lymph node macropha ges. Pressure-dependent gaps between lymphatic capillary endothelial c ells are thought to play the role of the size discrimination device al lowing larger particulates into the lymphatics and, eventually, into t he blood after increase of interstitial pressure caused by injection s ite massage. (C) 1998 Elsevier Science B.V.