Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis.
Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis.
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DOI：
10.1021/acsnano.7b01385
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发表时间：
2017-06-27
期刊：
影响因子：
17.1
通讯作者：
Kluza E
中科院分区：
文献类型：
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作者：
Beldman TJ;Senders ML;Alaarg A;Pérez-Medina C;Tang J;Zhao Y;Fay F;Deichmöller J;Born B;Desclos E;van der Wel NN;Hoebe RA;Kohen F;Kartvelishvily E;Neeman M;Reiner T;Calcagno C;Fayad ZA;de Winther MPJ;Lutgens E;Mulder WJM;Kluza E
透明质酸是一种生物活性聚合物，可以配制为纳米颗粒。在我们的研究中，我们的目的是通过使用透明质酸纳米粒子来探究动脉粥样硬化相关的炎症，并确定它们是否可以改善动脉粥样硬化。透明质酸纳米颗粒（HA-NP）是通过胺官能化低聚透明质酸（HA）与胆酸酯反应制备的，并用荧光或放射性标记进行标记。通过几种先进的显微镜方法在体外对 HA-NP 进行了表征。 HA-NP 的靶向特性和生物分布在 apoe-/- 小鼠中进行了研究，这些小鼠接受荧光或放射性标记的 HA-NP，并通过流式细胞术或核技术进行离体检查。此外，三只动脉粥样硬化兔子接受了 89Zr-HA-NP 并通过 PET/MRI 进行成像。 HA-NP 的治疗效果在 apoe-/- 小鼠中进行了研究，这些小鼠在 12 周的高脂饮食喂养期间每周接受 50 mg/kg HA-NP 的剂量。水合 HA-NP 约为。直径为90 nm，在水解条件下表现出非常稳定的形态。流式细胞术显示主动脉巨噬细胞对 Cy7-HA-NP 的摄取比正常组织巨噬细胞高 6 至 40 倍。有趣的是，局部和全身HA-NP-免疫细胞相互作用随着疾病进展而显着减少。 89Zr-HA-NPs 在动脉粥样硬化主动脉中诱导的放射性比野生型对照高 30%。兔子的 PET 成像显示标准化摄取值比肌肉高 6 倍。与对照组和游离 HA 治疗组相比，HA-NP 治疗组小鼠的斑块中巨噬细胞含量减少了 30%。总之，我们展示了 HA-NP 良好的靶向特性，可用于动脉粥样硬化相关炎症的 PET 成像。此外，我们还证明了 HA-NPs 在动脉粥样硬化中的抗炎作用。
Hyaluronan is a biologically active polymer, which can be formulated into nanoparticles. In our study, we aimed to probe atherosclerosis-associated inflammation by using hyaluronan nanoparticles and to determine whether they can ameliorate atherosclerosis. Hyaluronan nanoparticles (HA-NPs) were prepared by reacting amine-functionalized oligomeric hyaluronan (HA) with cholanic ester and labeled with a fluorescent or radioactive label. HA-NPs were characterized in vitro by several advanced microscopy methods. The targeting properties and biodistribution of HA-NPs were studied in apoe–/– mice, which received either fluorescent or radiolabeled HA-NPs and were examined ex vivo by flow cytometry or nuclear techniques. Furthermore, three atherosclerotic rabbits received 89Zr-HA-NPs and were imaged by PET/MRI. The therapeutic effects of HA-NPs were studied in apoe–/– mice, which received weekly doses of 50 mg/kg HA-NPs during a 12-week high-fat diet feeding period. Hydrated HA-NPs were ca. 90 nm in diameter and displayed very stable morphology under hydrolysis conditions. Flow cytometry revealed a 6- to 40-fold higher uptake of Cy7-HA-NPs by aortic macrophages compared to normal tissue macrophages. Interestingly, both local and systemic HA-NP–immune cell interactions significantly decreased over the disease progression. 89Zr-HA-NPs-induced radioactivity in atherosclerotic aortas was 30% higher than in wild-type controls. PET imaging of rabbits revealed 6-fold higher standardized uptake values compared to the muscle. The plaques of HA-NP-treated mice contained 30% fewer macrophages compared to control and free HA-treated group. In conclusion, we show favorable targeting properties of HA-NPs, which can be exploited for PET imaging of atherosclerosis-associated inflammation. Furthermore, we demonstrate the anti-inflammatory effects of HA-NPs in atherosclerosis.