Abstract
Macrophage inflammation and maturation into foam cells, following the engulfment of oxidized low-density lipoproteins (oxLDL), are major hallmarks in the onset and progression of atherosclerosis. Yet, chronic treatments with anti-inflammatory agents, such as methotrexate (MTX), failed to modulate disease progression, possibly for the limited drug bioavailability and plaque deposition. Here, MTX–lipid conjugates, based on 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), were integrated in the structure of spherical polymeric nanoparticles (MTX-SPNs) or intercalated in the lipid bilayer of liposomes (MTX-LIP). Although, both nanoparticles were colloidally stable with an average diameter of ∼200 nm, MTX-LIP exhibited a higher encapsulation efficiency (>70%) and slower release rate (∼50% at 10 h) compared to MTX-SPN. In primary bone marrow derived macrophages (BMDMs), MTX-LIP modulated the transcellular transport of oxLDL more efficiently than free MTX mostly by inducing a 2-fold overexpression of ABCA1 (regulating oxLDL efflux), while the effect on CD36 and SRA-1 (regulating oxLDL influx) was minimal. Furthermore, in BMDMs, MTX-LIP showed a stronger anti-inflammatory activity than free MTX, reducing the expression of IL-1β by 3-fold, IL-6 by 2-fold, and also moderately of TNF-α. In 28 days high-fat-diet-fed apoE–/– mice, MTX-LIP reduced the mean plaque area by 2-fold and the hematic amounts of RANTES by half as compared to free MTX. These results would suggest that the nanoenhanced delivery to vascular plaques of the anti-inflammatory DSPE-MTX conjugate could effectively modulate the disease progression by halting monocytes’ maturation and recruitment already at the onset of atherosclerosis.
Highlights
Similar results were reported by Alekseeva et al (2017) documenting a 4-fold improvement in drug bioavailability for the MTX-liposomes over the free drug.13Also, a few studies have started to show that the atheroprotective properties of MTX can be more effectively exploited by administering nanoparticles loaded with the drug rather than the free molecule. 14-15 For instance, MTX-loaded polymeric nanoparticles were shown by the authors to mitigate atherosclerotic progression in apolipoprotein-E-/- mice, fed with a high-fat diet (HFD). 16 accumulation of bloodborne nanoparticles into atherosclerotic plaques would increase the dose of MTX delivered to the inflamed arterial wall, avoiding side effects associated with systemic exposure
The MTX-loaded Spherical Polymeric Nanoparticles (MTX-Spherical Polymeric Nanoparticles (SPNs)) were realized via a single emulsion technique resulting in a poly(lacticco-glycolic acid) (PLGA) hydrophobic core that is externally stabilized by a lipid monolayer, including carboxyl-terminated DSPE-PEG molecules (Figure 1A)
It is here important to recall that the conjugate in the MTX-loaded Liposomes (MTX-LIP) provides a structural contribution in addition to the pharmacological function in that it is directly included into the double-lipid layer of the liposomes
Summary
Atherosclerosis is an inflammatory disorder affecting large and medium size arteries and is responsible for acute cardiovascular syndromes, such as myocardial infarction (MI) and stroke. 1 Immune cells play a key role in all the stages of the pathology, from endothelial dysfunction to plaque formation and rupture. 2 Atherosclerotic vascular lesions are established by the continuous infiltration of circulating monocytes into the arterial walls and their progressive maturation into macrophages and foam cells. 3 These are lipid-rich macrophages that have up-taken large amounts of oxidized low-density lipoproteins (oxLDL), mostly through specific surface receptors such as CD36 and SRA-1. 4 one strategy to prevent atherosclerotic plaque formation and progression relies on reducing vascular inflammation. 5-6Recently, methotrexate (MTX), which is a potent chemotherapeutic and anti-inflammatory agent, was proposed for the treatment of atherosclerosis in patients affected by chronic inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. 2 Atherosclerotic vascular lesions are established by the continuous infiltration of circulating monocytes into the arterial walls and their progressive maturation into macrophages and foam cells. 16 accumulation of bloodborne nanoparticles into atherosclerotic plaques would increase the dose of MTX delivered to the inflamed arterial wall, avoiding side effects associated with systemic exposure. Nanoparticles accumulation is supported by different and multiple mechanisms, including the direct nanoparticle uptake by phagocytic macrophages; the deposition within the diseased tissue due to favorable, local hydrodynamic conditions (recirculation area and low wall shear stresses), hyper-permeability of a dysfunctional endothelium and increased angiogenesis; 20-24 the direct plaque localization via molecular targeting; 25-28 and the nanoparticle uptake by circulating monocytes that would eventually infiltrate the plaque. Nanoparticles accumulation is supported by different and multiple mechanisms, including the direct nanoparticle uptake by phagocytic macrophages; the deposition within the diseased tissue due to favorable, local hydrodynamic conditions (recirculation area and low wall shear stresses), hyper-permeability of a dysfunctional endothelium and increased angiogenesis; 20-24 the direct plaque localization via molecular targeting; 25-28 and the nanoparticle uptake by circulating monocytes that would eventually infiltrate the plaque. 29-30
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