Mannosylated Polyrotaxanes for Increasing Cellular Uptake Efficiency in Macrophages through Receptor-Mediated Endocytosis
Mannosylated Polyrotaxanes for Increasing Cellular Uptake Efficiency in Macrophages through Receptor-Mediated Endocytosis
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DOI：
10.3390/molecules24030439
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发表时间：
2019-01
期刊：
影响因子：
4.6
通讯作者：
Kai Shibaguchi;A. Tamura;M. Terauchi;M. Matsumura;H. Miura;N. Yui
中科院分区：
文献类型：
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作者：
Kai Shibaguchi;A. Tamura;M. Terauchi;M. Matsumura;H. Miura;N. Yui
巨噬细胞在调节炎症和免疫反应以及慢性炎性疾病和癌症的发病机制中发挥重要作用。因此，靶向给药巨噬细胞是一种有效的治疗和诊断方法。我们之前研究了由多个环糊精（CDs）组成的聚轮烷（PRXs）在聚合物链上的治疗应用。在本研究中，我们设计了一种α-d-甘露糖修饰α-CD/聚乙二醇基PRX （Man-PRX）。研究了巨噬细胞样RAW264.7细胞通过与巨噬细胞甘露糖受体（MMR）相互作用摄取Man-PRX的情况。在mmr阳性的RAW264.7细胞中观察到细胞内Man-PRX摄取，但在mmr阴性的NIH/3T3细胞中可以忽略不计。此外，在游离α-d-甘露糖和抗MMR抗体的存在下，RAW264.7细胞内Man-PRX的摄取被显著抑制，这表明MMR参与了Man-PRX的细胞内摄取。RAW264.7细胞的极化对Man-PRX内化效率也有影响。这些结果表明，Man-PRX是通过与MMR特异性相互作用选择性靶向巨噬细胞的有效候选物。
Macrophages play an important role in the regulation of inflammation and immune response as well as the pathogenesis of chronic inflammatory diseases and cancer. Therefore, targeted delivery of therapeutic reagents to macrophages is an effective method for treatment and diagnosis. We previously examined the therapeutic applications of polyrotaxanes (PRXs) comprised of multiple cyclodextrins (CDs) threaded on a polymer chain and capped with bulky stopper molecules. In the present study, we designed an α-d-mannose-modified α-CD/poly(ethylene glycol)-based PRX (Man-PRX). The intracellular uptake of Man-PRX through the interaction with macrophage mannose receptor (MMR) in macrophage-like RAW264.7 cells was examined. Intracellular Man-PRX uptake was observed in MMR-positive RAW264.7 cells but was negligible in MMR-negative NIH/3T3 cells. In addition, the intracellular Man-PRX uptake in RAW264.7 cells was significantly inhibited in the presence of free α-d-mannose and an anti-MMR antibody, which suggests that MMR is involved in the intracellular uptake of Man-PRX. Moreover, the polarization of RAW264.7 cells affected the Man-PRX internalization efficiency. These results indicate that Man-PRX is an effective candidate for selective targeting of macrophages through a specific interaction with the MMR.