PLASMA-CLEARANCE AND BIODISTRIBUTION OF OXIDATIVELY MODIFIED TC-99M-BETA-VLDL IN RABBITS

The biodistribution and removal from plasma (measured as fractional cl earance rate, FCR, per hour) of native and oxidatively modified (99m)t echnetium-labeled beta-very low density lipoprotein (Tc-99m-beta-VLDL) were investigated in hypercholesterolemic (HC) and control (C) three- month old New Zealand rabbits. The intracellular accumulation of beta- VLDL labeled with Tc-99m was studied in vitro in THP-1 cells and monoc yte-derived macrophages isolated from rabbits. After intravenous injec tion into C rabbits, copper-oxidized D-VLDL (Tc-99m-ox-beta-VLDL) was cleared from the circulation faster (0.362 +/- 0.070/h) than native be ta-VLDL (Tc-99m-nat-beta-VLDL, 0.241 +/- 0.070/h). In contrast, the FC R of Tc-99m-ox-beta-VLDL in HC rabbits was lower (0.100 +/- 0.048/h) t han that of Tc-99m-nat-beta-VLDL (0.163 +/- 0.043/h). The hepatic upta ke of radiolabeled lipoproteins was lower in HC rabbits (0.114 +/- 0.0 71% injected dose/g tissue for Tc-99m-nat-beta-VLDL and 0.116 +/- 0.05 7% injected dose/g tissue for Tc-99m-ox-beta-VLDL) than in C rabbits ( 0.301 +/- 0.113% injected dose/g tissue for Tc-99m-nat-beta-VLDL and 0 .305 +/- 0.149% injected dose/g tissue for Tc-99m-ox-beta-VLDL). The u ptake of Tc-99m-nat-beta-VLDL and Tc-99m-ox-beta-VLDL by atherosclerot ic aorta lesions isolated from HC rabbits (Tc-99m-nat-beta-VLDL: 0.033 +/- 0.012% injected dose/g tissue and Tc-99m-ox-beta-VLDL: 0.039 +/- 0.017% injected dose/g tissue) was higher in comparison to that of non -atherosclerotic aortas from C rabbits (Tc-99m-nat-beta-VLDL: 0.023 +/ - 0.010% injected dose/g tissue and Tc-99m-ox-beta-VLDL: 0.019 +/- 0.0 10% injected dose/g tissue). However, Tc-99m-nat-beta-VLDL and (99)mTc -ox-beta-VLDL were taken up by atherosclerotic lesions at similar rate s. In vitro studies showed that both monocyte-derived macrophages isol ated from rabbits and THP-1 macrophages significantly internalized mor e Tc-99m-ox-beta-VLDL than Tc-99m-nat-beta-VLDL. These results indicat e that in cholesterol-fed rabbits Tc-99m-ox-beta-VLDL is slowly cleare d from plasma and accumulates in atherosclerotic lesions. However, alt hough the extent of in vitro uptake of Tc-99m-ox-beta-VLDL by macropha ges was high, the in vivo accumulation of this radiolabeled lipoprotei n by atherosclerotic lesions did not differ from that of Tc-99m-nat-be ta-VLDL.