Modulating Lipoprotein Transcellular Transport and Atherosclerotic Plaque Formation in ApoE-/- Mice via Nanoformulated Lipid- Methotrexate Conjugates
Modulating Lipoprotein Transcellular Transport and Atherosclerotic Plaque Formation in ApoE-/- Mice via Nanoformulated Lipid- Methotrexate Conjugates
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DOI：
10.1021/acsami.0c12202
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发表时间：
2020-08-26
影响因子：
9.5
通讯作者：
Decuzzi, Paolo
中科院分区：
文献类型：
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作者：
Di Francesco, Valentina;Gurgone, Danila;Decuzzi, Paolo
随着氧化低密度脂蛋白(OxLDL)的吞噬，巨噬细胞炎症和成熟为泡沫细胞是动脉粥样硬化发生和发展的主要标志。然而，抗炎药的慢性治疗，如甲氨蝶呤(MTX)，未能调节疾病的进展，可能是由于药物的生物利用度有限和斑块沉积。在这里，甲氨蝶呤-脂质结合物，基于1，2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)，被整合到球形聚合物纳米粒(MTX-SPN)的结构中或插入脂质体的脂质双层(MTX-LIP)中。两种纳米粒均具有胶体稳定性，平均粒径接近200 nm，但与MTX-SPN相比，MTX-LIP具有更高的包封率(70%)和更低的释药速率(10h释放率接近50%)。在原代骨髓来源的巨噬细胞(BMDM)中，MTX-LIP比游离MTX更有效地调节oxLDL的跨细胞转运，主要是通过诱导ABCA1(调节oxLDL外流)的2倍过表达，而对CD36和SRA-1(调节oxLDL内流)的影响很小。此外，在BMDM中，MTX-LIP显示出比游离MTX更强的抗炎活性，使IL-1β的表达减少了3倍，IL-6的表达减少了2倍，对TNF-α的表达也有适度的降低。在28天的高脂饮食喂养的ApoE(-/-)小鼠中，MTX-LIP与游离MTX相比，平均斑块面积减少了2倍，RANTES的血液量减少了一半。这些结果表明，抗炎DSPE-MTX结合物的纳米增强递送到血管斑块可以通过阻止单核细胞的成熟和募集而有效地调节疾病的进展，这些单核细胞在动脉粥样硬化开始时就已经存在。
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 similar to 200 nm, MTX-LIP exhibited a higher encapsulation efficiency (>70%) and slower release rate (similar to 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-1 beta by 3-fold, IL-6 by 2-fold, and also moderately of TNF-alpha. 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.