Enhanced biliary iron excretion with amphiphilic diethylenetriaminepentaacetic acid

Abstract

The elimination of toxic metal ions metabolically accumulated by patients remains a difficult clinical problem and a target of drug development. DTPA (diethylenetriaminepentaacetic acid) is a hydrophilic chelating agent with high affinity for divalent and trivalent metal ions including iron but with a limited ability to cross cell membranes for access to iron stores. In this study we have synthesized an amphiphilic form of this chelator-DTPA covalently linked to the phospholipid phosphatidylethanolamine (PE)--to produce a chelator that incorporates completely and stably into liposome membranes for efficient delivery to the liver and reticuloendothelial system. Biliary and urinary excretion of iron were studied in iron-loaded rats (n = 15) in association with a 2-hr intravenous infusion of sonicated liposomes of 1:1 amphiphilic phosphatidylethanolamine-DTPA/egg phosphatidylcholine (L-PE-DTPA) and compared with excretion obtained using equivalent amounts of water-soluble DTPA (alone or mixed with egg phosphatidylcholine liposomes [L-DTPA] as controls). For a 6-hr period, the administration of L-PE-DTPA resulted in approximately a 20-fold increase in biliary iron excretion (480 +/- 160 micrograms/6 hr, mean +/- S.D.) compared with that seen with DTPA (21.2 +/- 4.0 micrograms/6 hr) and L-DTPA (23.1 +/- 5.0 micrograms/6 hr) (p less than 0.05, analysis of variance). Urinary iron excretion was significantly decreased with L-PE-DTPA (41.5 +/- 38 micrograms/6 hr) compared with DTPA (154 +/- 110 micrograms/6 hr) and L-DTPA (86 +/- 17 micrograms/6 hr) (p less than 0.05). Combined biliary and urinary excretion of iron was three to four times greater with L-PE-DTPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Pre-clinical Evaluation of a Cyanine-Based SPECT Probe for Multimodal Tumor Necrosis Imaging

“…Our findings, in the dry ice assay, show that the specificity of [ 111 In]DTPA-HQ4 for necrotic cells was solely due to the presence of the HQ4 molecule, as the radiolabeled chelate [ 111 In]DTPA alone and free 111 In-Cl 3 did not show to bind to the dead cells. Although DTPA conjugation is likely to change the chemical and physico-chemical properties of HQ4, for example by increasing its overall hydrophylicity [57], it retained its necrosis avid- and fluorescent properties. We observed a clear difference in the signal-to-background (S/B) ratio of [ 111 In]DTPA-HQ4 between fluorescence- and radioactivity measurements.…”