Targeting zinc protoporphyrin liposomes to the spleen using reticuloendothelial blockade with blank liposomes.
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 heme-degrading 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 microns 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 mumol 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 mumol of aqueous ZnPP per kg or 10 mumol 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 mumol 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Hamori
C J
CJ
University of California, San Diego, School of Medicine, La Jolla 92037.
Lasic
D D
DD
Vreman
H J
HJ
Stevenson
D K
DK
D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D004337:Drug Carriers; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors; D006801:Humans; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000188:drug therapy / Q000378:metabolism; D008081:Liposomes; D008297:Male; D012157:Mononuclear Phagocyte System / Q000187:drug effects / Q000378:metabolism; D011524:Protoporphyrins / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism
D004337:Drug Carriers; D008081:Liposomes; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin