PHYSICOCHEMICAL AND DISPOSITION CHARACTERISTICS OF ANTISENSE OLIGONUCLEOTIDES COMPLEXED WITH GLYCOSYLATED POLY(L-LYSINE)

The disposition characteristics of a 20 mer antisense phosphodiester o ligonucleotide (PO) and its fully phosphorothioated derivative (PS) al one or complexed with glycosylated poly(L-lysine) (galactosylated poly lysine, Gal-PLL; mannosylated polylysine, Man-PLL) were studied in mic e in relation to their physicochemical characteristics. Good complex f ormation was obtained at a ratio of 1:0.6, w/w [oligonucleotides (ODNs )/carrier]. The 1:0.6 weight ratio of ODNs/Gal-PLL and ODNs/Man-PLL co mplexes had zeta potentials of -27 to -31 mV and mean particle size of 100 to 160 nm. After intravenous injection, S-35-labeled ODNs were el iminated rapidly from the circulation; however, their organ dispositio n characteristics depended on their type. Complex formation with glyco sylated PLL increased the hepatic uptake and decreased the urinary cle arance of these ODNs to a great extent. These complexes were taken up by both liver parenchymal cells (PC) and nonparenchymal cells (NPC). H owever, ODNs/Gal-PLL complexes showed a fairly high PC concentration, whereas ODNs/Man-PLL complexes distributed equally to both PC and NPC. The hepatic uptakes of PS/Gal-PLL and PS/Man-PLL complexes were parti ally inhibited by prior administration of Gal-BSA and Man-BSA, respect ively, suggesting their hepatic uptake via the respective receptor-med iated endocytosis. However, uptake by galactose receptors of Kupffer c ells, 5 potential, particle size, and Kupffer cell phagocytosis also s eem to influence their uptake process. In conclusion, this study illus trates that ODNs can be delivered to hepatocytes and macrophages via g alactose and mannose receptors, respectively. (C) 1997 Elsevier Scienc e Inc.