Subcutaneous administration of liposomes: a comparison with the intravenous and intraperitoneal routes of injection

Abstract

The development of long-circulating liposomes containing lipid derivatives of poly(ethylene glycol) (PEG), termed Stealth liposomes, has considerably improved the prospects for therapeutic applications of liposomal drug delivery systems. We have examined the pharmacokinetics and biodistribution of long-circulating, as compared to conventional, liposomes after subcutaneous (sc) administration in mice. Results obtained after subcutaneous administration were compared to those obtained after intravenous (iv) and intraperitoneal (ip) administration. Liposomes, following sc administration, appeared intact in the circulation subsequent 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) liposomes in the blood, with up to 30% of vivo label appearing in the blood 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 significant extent. The presence of PEG-DSPE and cholesterol was important for the in vivo stability of the liposome after sc administration. Although liposome levels were significantly higher in the draining lymph nodes after sc administration, levels associated with other tissues were proportionately reduced relative to the iv and ip routes of administration. Liposomes appeared in blood after ip and sc administration with half-lives of approx. 0.6 and 9 h, respectively, and subsequent to appearing in blood had similar biodistribution, pharmacokinetics and half-lives (20.4 h) to liposomes given by the iv route.