Polyamine-substituted gadolinium chelates: a new class of intracellular contrast agents for magnetic resonance imaging of tumors.
A new class of intracellular contrast agents (CA) for magnetic resonance imaging has been developed, based on Gd(DTPA) with two positively charged amide-linked substituents. Uptake of Gd(DTPA) into cultured tumor cell lines (B16 mouse melanoma, MH3924A Morris hepatoma) was below the detection limit while CA with the melanin-binding pharmacophore 2-(diethylamino)ethylamine reached intracellular concentrations of ca. 0.03 fmol/cell (ca. 20 microM) for melanoma and 0.02 fmol/cell for hepatoma (24 h at 10 microM CA). With the polyamine substituents bis(2-aminoethyl)amine or spermidine, CA uptake increased up to 3-fold for melanoma (0.083 fmol/cell) and 9-fold for hepatoma (0.18 fmol/cell). Uptake of polyamine-substituted CA was reduced by the polyamine transport inhibitor benzyl viologen. Molar relaxivities for three Gd-DTPA-polyamine complexes were in the range 5.6-6.9 for the free complex in solution and 7.7-23.5 s-1 mM-1 for Morris hepatoma cell pellets. T1-weighted magnetic resonance imaging at 2.35 T of rats with MH3924A tumors showed contrast enhancement in tumor at 1 and 24 h postinjection of polyamine-substituted CA.
Wolf
Markus
M
Department of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Hull
William E
WE
Mier
Walter
W
Heiland
Sabine
S
Bauder-Wüst
Ulrike
U
Kinscherf
Ralf
R
Haberkorn
Uwe
U
Eisenhut
Michael
M
D000818:Animals; D001692:Biological Transport; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis; D003287:Contrast Media / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019786:Gadolinium DTPA / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000648:ultrastructure; D011073:Polyamines / Q000138:chemical synthesis*; D051381:Rats; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D002614:Chelating Agents; D003287:Contrast Media; D011073:Polyamines; D019786:Gadolinium DTPA