New and more efficient multivalent glyco-ligands for asialoglycoprotein receptor of mammalian hepatocytes

New multi-valent, carbohydrate ligands that contain terminal N-acetylgalactosamine (GalNAc) or lactose (Lac) were prepared using a nitrilotriacetic acid (NTA) derivative of l-lysine as scaffold. Tri-valent structures were prepared by attaching an ω-amino glycoside of GalNAc or Lac to each of the three carboxyl groups of Nε-protected Nα-dicarboxymethyl-l-lysine. In addition, a hexa-valent lactoside was synthesized by attaching Nε-deprotected trivalent lactoside to each of the carboxyl group of Nα-(trifluoroacetamido)hexanoyl l-aspartic acid. Tri-valent GalNAc glycosides and the hexa-valent lactoside had high affinity (dissociation constants approaching nM) for rat hepatocytes. The hexa-valent lactoside, after de-Nε-protection, was modified with a chelator, diethylenetriaminepentaacetic acid (DTPA), through which a fluorescent or radioactive tag, such as europium or indium, can be firmly attached. Intravenous infusion of 111Indium-tagged hexa-valent lactoside to rats and mice resulted in nearly exclusive accumulation of radioactivity in the liver.

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