A molecular receptor-binding contrast agent for magnetic resonance imaging of the liver

Abstract

A gadolinium complex of polydiethylenetriamine pentaacetic acid polyneogalactosyl polylysine (Gd-DTPA-gal-PL) was developed and tested as a paramagnetic contrast agent for magnetic resonance (MR) imaging of the liver. The agent was designed for receptor-mediated uptake by the asialoglycoprotein receptor (ASGP-R), which is unique to hepatocytes and exhibits high specificity for galactose-terminated glycoconjugates. Polylysine was alkylated with a mixed anhydride of diethylenetriamine pentaacetic acid. This product was complexed with gadolinium and N-alkylated with 3-oxopropyl-1-thio-beta-D-galactopyranoside. With this reaction sequence, we prepared a gadolinium complex consisting of 2284 galactose groups and 858 chelators per polylysine having 2136 amino groups. Hepatic enhancement was tested by MR imaging of nine rats with liver-implanted mammary adenocarcinoma before and after injection of 20 x 10(-9) mol/kg Gd-DTPA858-gal2284-PL2136. The conjugate was labeled with technetium-99m and tested (1.5 x 10(-10) mol/kg) for hepatic specificity via nuclear imaging. Mean hepatic enhancement was 86% within 10 min and remained constant for 25 min. Hepatic relative intensity exceeded preinjection intensities by at least four times the standard deviation of the preinjection values (p < .01). The tumors, which are devoid of ASGP-R, did not exhibit significant enhancement (p > .1). The liver accumulated 90% of the technetium-99m-labeled conjugate. A molecular paramagnetic ligand to the asialoglycoprotein receptor has been developed for hepatocyte-specific MR contrast enhancement.