In the early progression of atherosclerosis, LDL migrates in the subendothelial space of the artery and plays an important role in foam cell formations of macrophages. LDL may serve as a carrier of site-specific delivery of drugs to atherosclerotic lesions. In this exploratory study, dexamethasone palmitate (DP) was incorporated in LDL, and an inhibitory effect of this complex on foam cell formations was examined. LDL was isolated from human plasma, and the DP-LDL complex was prepared by incubation in the presence of Celite 545. No degradation nor modification of LDL was observed. The DP/LDL molar ratio of the complex was 35-50:1. Foam cell formations of murine macrophages were induced by incubation with oxidized LDL. When macrophages were pretreated with the DP-LDL complex, accumulation of cholesterol ester in the macrophages induced by oxidized LDL, i.e., an index of foam cell formation, was decreased. These findings indicated that the DP-LDL complex showed similar characteristics to LDL, and the DP-LDL complex inhibited foam cell formations of macrophages in vitro. This study provides the basis for further study of the DP-LDL complex as a drug-carrier complex for treatment of atherosclerosis.

In order to confirm the efficacy of dexamethasone palmitate (DP)-low density lipoprotein (LDL) complex on experimental atherosclerosis in vivo, we examined whether DP-LDL complex could be effective for cholesterol ester accumulation in the aorta of atherogenic mice. Nonatherogenic and atherogenic mice were fed with normal and atherogenic diet for 14 weeks, respectively. Dexamethasone (DEX), lipid emulsion containing DP (DP-LE), or DP-LDL complex was intravenously injected once a week from 8 to 14 weeks. Cholesterol levels in serum and aorta in the atherogenic mice were significantly higher than those of nonatherogenic mice. Injection of DP-LDL complex significantly reduced cholesterol ester (CE) accumulation in the aorta of atherogenic mice. The reduction of CE accumulation in aorta treated with DP-LDL complexes was 10 and 100 times more potent than that with DP-LE and DEX, respectively. The radioactivity in the aorta of atherogenic mice treated with 3 H-DP-LDL complex was significantly higher than that with 3 H-DP-LE and 3 H-DEX at 24 h after injection. Even 7 d after injection, a significant amount of radioactivity was present only in the aorta of atherogenic mice treated with DP-LDL complex. This result suggests that DP-LDL complex is selectively delivered to the atherogenic lesions in the aorta of atherogenic mice, and then DP released from the complex inhibits CE accumulation in the aortic intima. Therefore, DP-LDL complex may be a good drug-carrier in drug delivery system for atherosclerosis.

We used low density lipoprotein (LDL) as a carrier of site-specific delivery of drugs to atherosclerotic lesions, prepared a dexamethasone palmitate (DP)-LDL complex, and examined the effect of the DP-LDL complex on foam cell formation of macrophages in vitro. LDL was isolated from human plasma and the DP-LDL complex was prepared by incubation in the presence of Celite 545. The complex contained about 50 mol of DP in 1 mol of LDL. When macrophages were incubated with LDL for 48 h, cholesterol ester was accumulated in the macrophages, indicating foam cell formation. This accumulation of cholesterol ester was significantly inhibited by incubation with the DP-LDL complex. The potency of the DP-LDL complex was similar to that of dexamethasone alone. The DP-LDL complex also significantly attenuated the accumulation of cholesterol ester induced by incubation with LDL prior to the incubation with the DP-LDL complex. These findings indicated that the DP-LDL complex showed similar characteristics to LDL, and the DP-LDL complex inhibited the foam cell formation of macrophages in in vitro experiments. This DP-LDL complex has a possibility as a drug-carrier complex for use in atherosclerosis.