Abstract
ABSTRACT: Metalloporphyrin inhibitors of heme oxygenase have been studied for use in the prevention of hyperbilirubinemia of the neonate. One report has suggested that incorporation of these drugs into liposomes can increase their localization to the spleen, dramatically reducing heme oxygenase activity in that important hemedegrading organ. We sought to further increase porphyrin delivery to the spleen by using reticuloendothelial blockade with blank liposomes 2 h before injection of 0.3 μm extruded zinc protoporphyrin liposomes (L-ZnPP). Control adult rats without hemolysis had splenic heme oxygenase activity of 1.07 ± 0.09 nmol carbon monoxide (CO)/h/mg protein. Rats treated with L-ZnPP alone had splenic heme oxygenase activity of 0.53 ± 0.16 nmol CO/h/mg protein 6 h after L-ZnPP dosing. However, rats treated with 1000 μmol of blank liposomes per kg to saturate the reticuloendothelial system 2 h before L-ZnPP administration had splenic heme oxygenase activity of 0.25 ± 0.16 nmol CO/ h/mg protein at t = 6 h, which is significantly less than that of the L-ZnPP alone group (p < 0.05). In adult rats treated with heat-damaged red blood cells (RBC) to simulate hemolysis, treatment with 10 μmol of aqueous ZnPP per kg or 10 μmol of untargeted L-ZnPP per kg did not produce a difference from control in total body bilirubin production as estimated by CO excretion. However, RBC-treated rats given 1000 μmol of blank liposomes per kg 2 h before L-ZnPP administration produced significantly less CO than control, aqueous ZnPP-treated, and untargeted L-ZnPP-treated rats from 8 to 12 h after RBC treatment. In addition, splenic heme oxygenase activity in RBC-treated rats receiving 10 μmol of targeted L-ZnPP per kg was completely eliminated 12 h after RBC treatment. These results indicate that targeting of L-ZnPP to the spleen with reticuloendothelial blockade leads to improved in vivo suppression of total body bilirubin production in adult rats treated with heat-damaged RBC. More complete inhibition of splenic heme oxygenase is the likely mechanism for this improved therapeutic effect.
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Hamori, C., Lasic, D., Vreman, H. et al. Targeting Zinc Protoporphyrin Liposomes to the Spleen Using Reticuloendothelial Blockade with Blank Liposomes. Pediatr Res 34, 1–5 (1993). https://doi.org/10.1203/00006450-199307000-00001
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DOI: https://doi.org/10.1203/00006450-199307000-00001