Clearance of liposomal gadolinium: In vivo decomplexation

Abstract

The contrast agents gadolinium-DTPA (diethylenetriaminepentaacetic acid), Gd-DOTA (tetraazacyclododecanetetraacetic acid), and Gd-HP-DO3A (1,4,7-tris[carboxymethyl]-10-[2' hydroxypropyl]-1,4,7,10-tetraazacyclododecane) are used in humans as extracellular contrast agents. Although free Gd+ ion is toxic, the intact Gd3+ complexes are rapidly excreted and are relatively nontoxic. Decomplexation with release of free gadolinium is a relevant clinical concern in patients with altered renal clearance. Blood pool contrast agents currently under development may have longer clearance half-lives and be more prone to decomplexation. The present study was designed to evaluate the clearance of liposomally encapsulated Gd3+ complexes (DTPA, DOTA, and HP-DO3A). The macrocyclic compounds had more rapid and complete clearance than DTPA (P less than .05). Parallel studies with carbon-14 and Gd-153-labeled complexes showed significant differences (P less than .05) in the amount of these isotopes retained in the heart, kidney, lungs, and spleen, providing strong supportive evidence for in vivo decomplexation.

Magnetic Resonance Imaging (MRI) Contrast Agents for Tumor Diagnosis

“…One factor contributing to the enhanced targeting capability is the enhanced permeability and retention (EPR) effect owing to accumulation of complexes of carriers and low molecular weight T 1 contrast agents, which are larger, in tumors with loosely vascular structures [29]. However, the possible release of free Gd 3+ was observed from some liposome loaded with low molecular weight T 1 MRI contrast agent, which showed a long retention time [30]. Therefore, the safety issues of the complex of carriers and low molecular weight T 1 contrast agent should be taken into account as well.…”

Lipid peptide nanocomplexes for gene delivery and magnetic resonance imaging in the brain

“…Gadolinium contrast agents based on the macrocyclic gadolinium chelator, DOTA could be used in future studies in the same LPD format which would be far more kinetically stable than acyclic gadolinium chelators, making them more persistent for imaging purposes and less toxic in vivo [26]. However, the DTPA reagent used here was adequate for proof of concept studies.…”

Intracerebral Diffusion of Paramagnetic Cationic Liposomes Containing Gd(DTPA)2- Followed by MRI Spectroscopy: Assessment of Patternc Diffusion and Time Steadiness of a Non-Viral Vector Model

“…Different strategies may be used when preparing paramagnetic liposomes, as the metal chelate can be encapsulated within the aqueous phase of the liposome, be covalently attached to the liposome surface or be incorporated into the membrane (2,14). for MRI applications (10,31), for in vivo applications two more aspects should be considered: the first concerns the aqueous interior of the liposome that should likely be isotonic in respect to biological fluids, the second regards the Gd(III) paramagnetic complex that must be thermodynamically stable and kinetically inert as the free Gd(III) cation is toxic. This latter aspect is overcome by using the wellknown and characterized paramagnetic contrast agent Gd(III) diethylenetriamine pentaacetic acid Gd(DTPAr-that acts as an effective extracellular fluid contrast agent for MRI.…”