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


METHODS
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.


RESULTS
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.


CONCLUSIONS
A molecular paramagnetic ligand to the asialoglycoprotein receptor has been developed for hepatocyte-specific MR contrast enhancement.
Vera
D R
DR
Department of Radiology, University of California, Davis, Medical Center, Sacramento, USA.
Buonocore
M H
MH
Wisner
E R
ER
Katzberg
R W
RW
Stadalnik
R C
RC
D000230:Adenocarcinoma / Q000175:diagnosis* / Q000378:metabolism; D000818:Animals; D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins / Q000378:metabolism; D003287:Contrast Media / Q000138:chemical synthesis / Q000378:metabolism*; D005260:Female; D019786:Gadolinium DTPA / Q000138:chemical synthesis / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000175:diagnosis* / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009368:Neoplasm Transplantation; D011107:Polylysine / Q000138:chemical synthesis / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013667:Technetium
D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D003287:Contrast Media; D011956:Receptors, Cell Surface; C110138:gadolinium diethylenetriamine pentaacetic acid polygalactosyl polylysine; D011107:Polylysine; D013667:Technetium; D019786:Gadolinium DTPA