Increased uptake of folate conjugates by activated macrophages in experimental hyperlipemia

Abstract

In the pathogenesis of atherosclerosis, macrophages become activated and play a crucial role in plaque formation. Activated synovial macrophages have recently been shown to express receptors for folic acid. We have determined whether activated macrophages also over-express folate receptor (FR) in atherosclerosis. Most normal cells express little or no FR, and, if FR is present on activated macrophages, folate-linked compounds and drugs could be selectively targeted to those cells that do express FR. To evaluate the FR on macrophages of atherosclerotic animals, golden Syrian hamsters were maintained on a hyperlipidemic diet until extensive vascular lesions had developed. Uptake of folic acid conjugated to fluorescent tags was then examined in tissue fragments from lesion-prone areas, and peritoneal activated macrophages were harvested from the same animals. Spectrofluorimetric and fluorescence microscopic analyses showed a significantly greater uptake of folate-conjugates by peritoneal macrophages of hyperlipidemic hamsters compared with those of hamsters fed a normal or folate-deficient diet. Systemically administered folate-fluorescent conjugates were found to accumulate as bright spots in protrusions of atherosclerotic plaques populated by macrophages, whereas a low level of fluorescence was detected uniformly dispersed across the lesion. The uptake of the folate conjugate by U937 macrophage cells grown in a high-lipid culture medium was significantly higher than in controls. Our data thus indicate that hyperlipidemic conditions induce an increased uptake of folate attributable to the over-expression of FRs on activated macrophages. This increase in FR expression can be exploited to deliver folate-linked compounds selectively to atherosclerotic lesions.

Imaging of Atherosclerosis in Apoliprotein E Knockout Mice: Targeting of a Folate-Conjugated Radiopharmaceutical to Activated Macrophages

“…5). These observations are consistent with previous histologic data on atherosclerotic heart valves from Syrian golden hamsters, which suggested that lipidladen macrophage foam cells can be readily targeted with folate-Texas Red (26).…”

“…Finally, together with the previously published data on osteoarthritis (12) and rheumatoid arthritis (14,23), the evidence presented here documents a third inflammatory disease that can be visualized with an FR-targeted radioimaging agent (26,40). Because many other inflammatory diseases are also characterized by a localized accumulation of activated macrophages, it will be important to determine whether similar folate conjugates might prove useful in imaging these other inflammatory diseases as well.…”

Cholesterol as a bilayer anchor for PEGylation and targeting ligand in folate‐receptor‐targeted liposomes

“…It is also possible that folate-PEG-Chol targeted liposomes were more easily captured by the FR on activated macrophage, which can be utilized for treatment chronic inflammatory diseases such as rheumatoid arthritis. [67][68][69][70] In summary, we have prepared and evaluated FR-targeted liposomes incorporating cholesterol derivatives mPEG-Chol and F-PEG-Chol. The particle properties, such as the morphology, stability, in vitro release, targeting efficacy, and in vivo circulation were evaluated in parallel with liposomes containing DSPE-anchored derivatives.…”

Endothelial cells and macrophages, partners in atherosclerotic plaque progression

“…Our recent studies on animal hyperlipidemic models demonstrated increased uptake of folate conjugates by activated macrophages The systemically administered folatefluorescent conjugates accumulated in protrusions of atherosclerotic plaques populated by macrophages, suggesting that activated macrophages can be efficiently targeted ''in vivo'' by using folate conjugate (Antohe et al, 2005a). Extensive atherosclerotic lesions were detected in sections of the aortic arch and cardiac valves that were packed with lipid deposits as revealed by staining with Oil Red O ( Figure 1a).…”