Paramagnetic liposomes containing amphiphilic bisamide derivatives of Gd-DTPA with aromatic side chain groups as possible contrast agents for magnetic resonance imaging

Abstract

Three amphiphilic DTPA bisamide derivatives containing long-chain phenylalanine esters (with 14, 16 and 18 carbon atoms in the alkyl chain) were synthesized and their corresponding gadolinium(III) complexes were prepared. The attempts to form paramagnetic micelles carrying the gadolinium(III) complexes yielded unstable or polydisperse micelles implying that the presence of the bulky aromatic side groups in the amphiphilic Gd-DTPA bisamide complexes results in an inefficient packing of the paramagnetic complex into micelles. All complexes were efficiently incorporated into liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), yielding stable and monodisperse paramagnetic liposomes. All liposomes had a comparable size, typically between 120 and 160 nm. As a result of the reduced mobility of the gadolinium(III) complexes, solutions of these supramolecular structures show a higher relaxivity than solutions of Gd-DTPA. However, the relaxivity gain is lower compared to compounds consisting of purely aliphatic chains of the same length, most likely due to the less efficient packing or increased local mobility of the gadolinium(III) complex. In the case of the Gd-DTPA bisamide complex with 18 carbon atoms, the immobilization inside the liposomal structure is less effective, probably because the aliphatic chains of the complex are longer than the alkyl chains of the DPPC host, resulting in a relatively high local mobility. The paramagnetic liposomes containing the Gd-DTPA bisamide complexes with 14 carbon atoms showed the highest relaxivity because the optimal length match between the hydrophobic chains of the DPPC and the ligand allowed very efficient packing of the paramagnetic complex into the liposome.