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Small unilamellar liposomes as magnetic resonance contrast agents loaded with paramagnetic Mn-, Gd-, and Fe-DTPA—stearate complexes

1989; Elsevier BV; Volume: 49; Issue: 3 Linguagem: Inglês

10.1016/0378-5173(89)90349-9

1873-3476

R.A. Schwendener, R. Wüthrich, Stefan Duewell, G. Westera, Gustav K. von Schulthess,

Nanoparticle-Based Drug Delivery

Small unilamellar liposomes were used as carriers for paramagnetic ions to enhance proton relaxation times for magnetic resonance imaging (MRI). The metal ions Fe3+, Gd3+ and Mn2+ were complexed to liposomes containing various amounts (20–60 mol%) of the lipophilic chelator diethylenetriamine pentaacetic acid (DTPA)-sterate (DTPA-SA). The Mn- and Gd-DTPA-SA liposomes were stable for more than two months and had a mean diameter of 26–36 nm, whereas for the Fe-DTPA-SA liposomes, vesicle sizes up to 2 μm were obtained. Due to their large size the Fe-DTPA-SA liposomes were not further studied. The efficiency of metal complexing averaged at 53 ± 16%, suggesting that the binding of the metal ions is restricted to the outer liposome surface. The complexing capacity was 3.5–11 μ mol, corresponding to 0.2–0.6 mg manganese or 0.55–1.7 mg gadolinium per ml liposomes. In vitro release of metal ions was very low, namely 0.4% for gadolinium, 1.8% for manganese and 5% for iron, determined 5 days after complex formation. Pharmacokinetics and organ distribution of radioactive 54Mn and 153Gd-DTPA-SA liposomes (0.03 mM/kg b.wt.) in rats revealed that approximately 35% of the Mn-liposomes were present in the liver after 30–60 minutes with more than 80% eliminated after 24 h. Mn-DTPA-SA was eliminated from the liver by biphasic kinetics with t12(1) = 20 min and t12(2) = 10 h Different results were obtained with Gd-DTPA-SA liposomes with a slower liver absorption over 2–4 h (35–60%) and a slow elimination with t12(2) = 80 h. Eight days after injection, 17% of the Gd-DTPA-SA could still be detected in the liver. Both complexes are predominantly eliminated through the hepato-biliary route. The very low metal concentrations found in the kidneys suggest that the metal complexes remain stable. Imaging experiments in rats showed that Mn-DTPA-SA liposomes at 0.03 mM/kg b.wt. gave a signal enhancement on T1 weighted images making the liver as bright as fat tissue. Images taken with Gd-DTPA-SA liposomes at the corresponding concentration gave a smaller, but still significant liver signal intensity increase. The DTPA-SA liposomes used as ligands for paramagnetic metals proved to be very efficient signal enhancers of the reticuloendothelial system (RES), mainly for the liver. The Mn-DTPA-SA lipomes in particular, produce a very strong signal enhancement and due to their fast elimination they might represent a viable contrast agent for MR-imaging of the upper abdomen.