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-ß), 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-ß, 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.

TPGS modified nanoliposomes as an effective ocular delivery system to treat glaucoma.

The aim of this study is to investigate the potential of D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) modified nanoliposomes as an ophthalmic delivery system of brinzolamide (Brz) for glaucoma treatment. The Brz loaded nanoliposomes containing TPGS (T-LPs/Brz) were firstly developed by a thin-film dispersion method. The average particle size was 96.87 ±â€¯4.43 nm. The entrapment efficiency of the Brz was 95.41 ±â€¯3.03% and the drug loading was 4.00 ±â€¯0.13%. T-LPs/Brz exhibited obvious sustained release of Brz; in stark contrast to the normal liposomes of Brz (LPs/Brz) and the commercial formulation AZOPT® (Brz ophthalmic suspension, Brz-Sus). Enhanced trans-corneal transport of Brz was achieved with T-LPs/Brz. Compared with both Brz-Sus and LPs/Brz, the apparent permeability coefficient (Papp) of T-LPs/Brz was 10.2 folds and 1.38 folds higher, respectively. Moreover, T-LPs/Brz extended the cornea residence of Brz. White New Zealand rabbits treated with T-LPs/Brz had 3.18 folds and 1.57 folds Brz concentration 2 h after treatment than Brz-Sus and LPs/Brz, respectively. Further pharmacodynamic studies showed that T-LPs/Brz maintained an effective intraocular pressure (IOP) reduction from 3 h to 11 h after administration, while Brz-Sus and LPs/Brz presented effective IOP decreases from 3 h to 6 h and 3 h to 8 h respectively. The preliminary safety evaluation demonstrated that T-LPs/Brz had no significant side effects; specifically, no cornea damage and eye irritation. All the results indicated that TPGS modified nanoliposomes were a promising ocular delivery carriers for Brz to treat glaucoma. As such, T-LPs/Brz might be worthy of further translational study.