SUBCUTANEOUS ADMINISTRATION OF LIPOSOMES - A COMPARISON WITH THE INTRAVENOUS AND INTRAPERITONEAL ROUTES OF INJECTION

The development of long-circulating liposomes containing lipid derivat ives of poly(ethylene glycol) (PEG), termed Stealth(R) liposomes, has considerably improved the prospects for therapeutic applications of li posomal drug delivery systems. We have examined the pharmacokinetics a nd biodistribution of long-circulating, as compared to conventional, l iposomes after subcutaneous (sc) administration in mice. Results obtai ned after subcutaneous administration were compared to those obtained after intravenous (iv) and intraperitoneal (ip) administration. Liposo mes, following sc administration, appeared intact in the circulation s ubsequent to moving down the lymph node chains that drain the site of injection. Liposomes containing PEG-distearoylphosphatidylethanolamine (PEG-DSPE) resulted in the highest levels of small (80-90 nm) liposom es in the blood, with up to 30% of in vivo label appearing in the bloo d at 12 to 24 h post-injection. In the absence PEG-DSPE approx. 4-fold lower levels of liposomes were found in the blood. Small size of the liposomes was critical to their ability to move into the circulation, with liposomes above 110-120 nm not appearing in blood to any signific ant extent. The presence of PEG-DSPE and cholesterol was important for the in vivo stability of the liposome after sc administration. Althou gh liposome levels were significantly higher in the draining lymph nod es after sc administration, levels associated with other tissues were proportionately reduced relative to the iv and ip routes of administra tion. Liposomes appeared in blood after ip and sc administration with half-lives of approx. 0.6 and 9 h, respectively, and subsequent to app earing in blood had similar biodistribution, pharmacokinetics and half -lives (20.4 h) to liposomes given by the iv route.