Site-specific delivery of oligonucleotides to hepatocytes after systemic administration.
We previously complexed ODN with galactosylated poly( l-lysine) (Gal-PLL) to enhance its site-specific delivery to hepatocytes. To avoid the use of polycations, in this study we conjugated galactosylated poly(ethylene glycol) (Gal-PEG (MW of PEG: 3486 +/- 500 Da)) to ODN via an acid-labile ester linkage of beta-thiopropionate. Following tail vein injection into rats, Gal-PEG- 33P-ODN rapidly cleared from the circulation and 60.2% of the injected dose accumulated in the liver at 30 min postinjection, which was significantly higher than that deposited after injection of 33P-ODNs. The plasma concentration versus time profile of Gal-PEG- 33P-ODN was biphasic, with 4.38 +/- 0.36 min as t1/2 of distribution and 118.61 +/- 22.06 min as t1/2 of elimination. Prior administration of excess Gal-BSA decreased the hepatic uptake of Gal-PEG- 33P-ODN from 60.2% to 35.9%, suggesting galactose triggers the asialoglycoprotein receptor-mediated endocytosis of Gal-PEG- 33P-ODN by hepatocytes. A large proportion of the injected Gal-PEG- 33P-ODN was taken up by the hepatocytes as evidenced by determination of radioactivity in the digested liver cells upon liver perfusion and separation by centrifugation on a Nycodenz gradient. In conclusion, Gal-PEG-ODN conjugate may be used for treating a variety of liver diseases.
Zhu
Lin
L
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Ye
Zhaoyang
Z
Cheng
Kun
K
Miller
Duane D
DD
Mahato
Ram I
RI
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D004705:Endocytosis / Q000187:drug effects; D020862:GC Rich Sequence; D005690:Galactose / Q000378:metabolism; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013623:Tail
D009841:Oligonucleotides; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; D005690:Galactose