โ Scribed by Dr. Paul C. Adams; Edward Lin; Kathryn R. Barber; Chris W. M. Grant
No coin nor oath required. For personal study only.
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 af6nity 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-DTPNegg phosphatidylcholine (L-PE-DTPA) and compared with excretion obtained using equivalent amounts of watersoluble 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 pg/6 hr, mean +-S.D.) compared with that seen with DTPA (21.2 f 4.0pg/6 hr) and L-DTPA (23.1 f 5.0 pg/6 hr) (p < 0.05, analysis of variance). Urinary iron excretion was significantly decreased with L-PE-DTPA (41.5 2 38 pg/6 hr) compared pg/6 hr) (p c 0.05). Combined biliary and urinary excretion of iron was three to four times greater with L-PE-DTPA. This study suggests that the use of a highly water-insoluble amphiphilic form of DTPA as sonicated liposomes altered the route and extent of delivery of the chelator to the iron stores, resulting in a significant increase in biliary iron excretion. (HEPA-with DTPA (154 f 110 pg/6 hr) and L-DTPA (86 * 17
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