CoII Complexes as Liposomal CEST Agents

Three paramagnetic Co^II macrocyclic complexes containing 2‐hydroxypropyl pendant groups, 1,1′,1′′,1′′′‐(1,4,8,11‐tetraazacyclotetradecane‐1,4,8,11‐tetrayl)tetrakis‐ (propan‐2‐ol) ([Co(L1)]²⁺, 1,1′‐(4,11‐dibenzyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐diyl)bis(propan‐2‐ol) ([Co(L2)]²⁺), and 1,1′‐(4,11‐dibenzyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐diyl)bis(octadecan‐2‐ol) ([Co(L3)]²⁺) were synthesized to prepare transition metal liposomal chemical exchange saturation transfer (lipoCEST) agents. In solution, ([Co(L1)]²⁺) forms two isomers as shown by ¹H NMR spectroscopy. X‐ray crystallographic studies show one isomer with 1,8‐pendants in cis‐configuration and a second isomer with 1,4‐pendants in trans‐configuration. The [Co(L2)]²⁺ complex has 1,8‐pendants in a cis‐configuration. Remarkably, the paramagnetic‐induced shift of water ¹H NMR resonances in the presence of the [Co(L1)]²⁺ complex is as large as that observed for one of the most effective Ln^III water proton shift agents. Incorporation of [Co(L1)]²⁺ into the liposome aqueous core, followed by dialysis against a solution of 300 mOsm L^?1 produces a CEST peak at 3.5 ppm. Incorporation of the amphiphilic [Co(L3)]²⁺ complex into the liposome bilayer produces a more highly shifted CEST peak at ?13 ppm. Taken together, these data demonstrate the feasibility of preparing Co^II lipoCEST agents.     

Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water 1H NMR Shift

Mobile proton‐containing solutes can be detected by MRI by the chemical exchange saturation transfer (CEST) method. CEST sensitivity is dramatically enhanced by using, as exchanging protons, the water molecules confined inside liposomes, shifted by a paramagnetic shift reagent. The chemical shift of the intraliposomal water resonance (δ^IL) is affected by the overall shape of the supramolecular system. δ^IL of a spherical LipoCEST acts as a sensitive reporter of the distribution of streptavidin proteins anchored at the liposome surface by biotinylated phospholipids. This finding prompted the design of a MMP‐2 responsive LipoCEST agent as the streptavidin moieties can be released from the liposome surfaces when a properly tailored enzyme‐cleavable peptide is inserted on the phospholipids before the terminal biotin residues. δ^IL reports on the overall changes in the supramolecular architecture associated to the cleavage carried out by MMP‐2.