Lanthanide DO3A-Complexes Bearing Peptide Substrates: The Effect of Peptidic Side Chains on Metal Coordination and Relaxivity

Two DO3A-type ligands conjugated to substrates of urokinase (L3) and caspase-3 (L4) via a propyl-amide linker were synthesized and their lanthanide(III) (Ln3+) complexes studied. A model compound without peptide substrate (L2) and an amine derivative ligand mimicking the state after enzymatic cleavage (L1) were also prepared. Proton Nuclear Magnetic Relaxation Dispersion (NMRD) profiles recorded on the gadolinium(III) (Gd3+) complexes, complemented with the assessment of hydration numbers via luminescence lifetime measurements on the Eu3+ analogues, allowed us to characterize the lanthanide coordination sphere in the chelates. These data suggest that the potential donor groups of the peptide side chains (carboxylate, amine) interfere in metal coordination, leading to non-hydrated LnL3 and LnL4 complexes. Nevertheless, GdL3 and GdL4 retain a relatively high relaxivity due to an important second-sphere contribution generated by the strongly hydrophilic peptide chain. Weak PARACEST effects are detected for the amine-derivative EuL1 and NdL1 chelates. Unfortunately, the GdL3 and GdL4 complexes are not significantly converted by the enzymes. The lack of enzymatic recognition of these complexes can likely be explained by the participation of donor groups from the peptide side chain in metal coordination.

The Positive Influence of Therapeutic Agent on Relaxivities of Gadolinium-Loaded Liposomal Theranostics

This study investigates changes in the MRI contrast properties of Gd(III)-containing paramagnetic liposomes following the incorporation of photosensitizing agent (ZnPc—zinc phthalocyanine). It provides identification of mechanisms responsible for enhancement of proton relaxation rate and hence, the increased both r1 and r2 relaxivities. Five liposomal formulations, containing fatty acids derivatives of Gd(III) salt and hydrophobic ZnPc, were synthesized. NMRD profiles of liposomal solutions (magnetic field range from 0.0002 to 9.4 T) were obtained and Modified Florence model was applied. The contrast properties of the model drug itself was separated from the lipid bilayer deformation influence, caused by its incorporation. The latter resulted, among other, in optimization of an apparent water exchange correlation time. As Gd(III) is located in the outer and inner lipid layers, some of the Gd(III) chelates are localized in aqueous interior of the liposomes, thus their contrasting efficiency depends on the water exchange rate through the membrane. The proposed approach raises the possibility of reducing the amount of potentially harmful contrast media based on gadolinium, by taking into account the increase of the relaxation effect caused by other components of the system.