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Received March 18, 1997; accepted July 17, 1997
Purpose. The aim of the present paper was to assess the effect of inclusion of distearoylphosphatidylethanolamine-poly(ethyleneglycol) (DSPE-PEG) into liposomal bilayers on the lymphatic uptake and lymph node localization of liposomes after subcutaneous administration.
Methods. [3H]-Cholesteryloleylether labeled liposomes of various composition and sizes were injected s.c. into the dorsal side of the foot of rats. At several time-points after injection, blood levels of liposomes were determined. Lymphatic uptake from the s.c. site of injection and lymph node localization in regional lymph nodes were determined at the end of the 52 h observation period.
Results. The results demonstrate that inclusion of DSPE-PEG into several types of liposomes has only a modest effect on lymphatic uptake. Also lymph node localization is only slightly affected by PEGmediated steric stabilization.
Conclusions. Factors other than the presence of a steric barrier are more important in determining lymphatic uptake from the s.c. injection site. The observation that lymph node localization was only slightly affected by PEG-coating strongly suggests that macrophage uptake is not the only important mechanism of lymph node localization of s.c. administered liposomes.
KEY WORDS: liposomes; subcutaneous; lymphatic disposition; steric stabilization.
ABBREVIATIONS: chol, cholesterol; DPPC, dipalmitoylphosphatidylcholine; DPPG, dipalmitoylphosphatidylglycerol; DSPE, distearoylphosphatidylethanolamine; EPC, egg-phosphatidylcholine; EPG, eggphosphatidylglycerol; i.m., intramuscular; MPS, mononuclear phagocyte system; PEG, poly(ethyleneglycol); s.c., subcutaneous.
INTRODUCTION
The ability of the lymphatic system to take up colloidal particles from interstitial spaces has raised interest to use colloids, such as liposomes, for the delivery of diagnostic and therapeutic agents to regional lymph nodes following local administration. The subcutaneous (s.c.) route of administration has been most extensively investigated for delivery of particulates to the lymphatic system (1-3). Particles up to about 0.15 (Am in diameter are transported from the s.c. injection site into the lymphatic capillaries and may localize in regional lymph nodes, whereas larger particles are trapped within the s.c. inter stitial space for a long period of time (4,5). However, even lymphatic uptake and lymph node localization of small-sized particles is incomplete. Previous studies have demonstrated that lymphatic uptake and lymph node localization of small (0.07 |jim) liposomes were typically about 60% and 1 % of the injected dose, respectively (1).
The incomplete lymphatic uptake of s.c. administered particles from the injection...