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J Biomed Nanotechnol. 2019 Jan 1;15(1):42-61. doi: 10.1166/jbn.2019.2676.

Folate-Modified Liposomes Loaded with Telmisartan Enhance Anti-Atherosclerotic Potency for Advanced Atherosclerosis in ApoE-/- Mice.


For the effective inhibition of atherosclerotic plaque rupture, there is an urgent need to develop a carrier which can specifically deliver the therapeutic agents to atherosclerotic lesions. Since the representative hallmark of plaques in advanced atherosclerosis is the large number of macrophages which highly upregulate folate receptor beta (FR-β), we herein investigated the potential of folate-modified liposomes (FA-P-LP) as the carrier for active targeting of atherosclerotic plaques. In vitro cellular uptake tests, FA-P-LP exhibited an enhanced uptake in activated RAW264.7 macrophages with high expression of FR-β, whereas this enhanced effect was dramatically diminished when the cells were pretreated with excess amount of free folate, indicating that FA-P-LP were mainly taken up by the receptor-mediated endocytosis. From the in vivo distribution assay, it was confirmly demonstrated that FA-P-LP significantly accumulated in atherosclerotic lesions and were co-localized with macrophages within plaques. Thereafter, we utilized the FA-P-LP to deliver an angiotensin receptor blocker (ARB), telmisartan (Tel), to macrophages in atherosclerotic plaques and evaluated their therapeutic effects on plaque destabilization. After 12 weeks treatment in ApoE-/- mice with established atherosclerosis, FA-P-LP/Tel exerted a marked improvement in key advanced plaque properties without affecting the plasma lipid level and blood pressure. These beneficial effects include the regression of atherosclerotic plaques possibly attributing to the enhanced cellular cholesterol efflux and reduced macrophage infiltration, an increase in the protective collagen layer overlying lesions resulting from suppression of collagenase activity and decrease in matrix 2/9 (MMP 2/9) expression, suppression of oxidative stress, and a reduction in plaque necrosis and calcification. Thus, administration of Tel in a targeted liposome could stabilize the advanced atherosclerotic lesions independent of lipid lowering and blood pressure decrease. In conclusion, FA-P-LP could effectively home to the atherosclerotic lesion through the active targeting mechanism after systemic administration, indicating their high potential as the carrier for atherosclerosis therapy. Together, the FA-P-LP/Tel would be considered as a promising nanotherapeutic approach to prevent plaque rupture, providing an alternative regimen for clinical treatment of advanced atherosclerosis.

[Indexed for MEDLINE]

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