Supramolecular assembly of an amphiphilic GdIII chelate: tuning the reorientational correlation time and the water exchange rate

In this paper we report the synthesis and the characterization of the novel ligand H5EPTPA-C16 ((hydroxymethylhexadecanoyl ester)ethylenepropylenetriaminepentaacetic acid). This ligand was designed to chelate the GdIII ion in a kinetically and thermodynamically stable way while ensuring an increased water exchange rate (kex) on the GdIII complex due to steric compression around the water binding site. The attachment of a palmitic ester unit to the pendant hydroxymethyl group on the ethylenediamine bridge yields an amphiphilic conjugate that forms micelles in aqueous solution with a long tumbling time (R). The critical micelle concentration (CMC = 0.34 mM) of the amphiphilic [Gd(EPTPA-C16)(H2O)]2- chelate was determined by variable concentration proton relaxivity measurements. A global analysis of the data obtained in variable temperature and multiple field 17O NMR, and 1H NMRD measurements allowed the determination of parameters governing relaxivity for [Gd(EPTPA-C16)(H2O)]2-; this is the first time that paramagnetic micelles with optimized water exchange are investigated. The water exchange rate was found to be kex298 = 1.7×108 s-1, very similar to that previously reported for the nitrobenzyl derivative [Gd(EPTPA-bz-NO2)(H2O)]2- (kex298 = 1.5×108 s-1). The rotational dynamics of the micelles was analysed using the Lipari-Szabo approach. The micelles formed in aqueous solution show a considerable flexibility, with a local rotational correlation time of the GdIII segments, lO298 = 330 ps, being much shorter than the global rotational correlation time of the supramolecular aggregates, gO298 = 2100 ps. This internal flexibility of the micelles is responsible for the only limited increase of the proton relaxivity observed on micelle formation (r1 = 22.59 mM-1s-1 for the micelles vs. 9.11 mM-1s-1 for the monomer chelate (20 MHz; 25°C)).Fundação para a Ciência e a Tecnologia (FCT) - POCTI/QUI/47005/2002). EU Cost Action D18 "Lanthanide chemistry for diagnosis and therapy". Swiss National Science Foundation. Swiss Federal Office for Education and Science

Liposomes as a gene delivery system

Gene therapy is an active field that has progressed rapidly into clinical trials in a relatively short time. The key to success for any gene therapy strategy is to design a vector able to serve as a safe and efficient gene delivery vehicle. This has encouraged the development of nonviral DNA-mediated gene transfer techniques such as liposomes. Many liposome-based DNA delivery systems have been described, including molecular components for targeting given cell surface receptors or for escaping from the lysosomal compartment. Another recent technology using cationic lipids has been evaluated and has generated substantial interest in this approach to gene transfer