Optimal structural design of mannosylated nanocarriers for macrophage targeting.
Optimal structural design of mannosylated nanocarriers for macrophage targeting.
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DOI：
10.1016/j.jconrel.2014.09.006
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发表时间：
2014-11-28
期刊：
影响因子：
--
通讯作者：
Sinko PJ
中科院分区：
文献类型：
--
作者：
Chen P;Zhang X;Jia L;Prud'homme RK;Szekely Z;Sinko PJ
巨噬细胞参与许多疾病，如HIV感染/AIDS、结核病、肿瘤发展和动脉粥样硬化。巨噬细胞具有几种细胞表面受体（例如，甘露糖受体，MR），其可用作纳米载体（NC）的药物递送细胞入口。在这项研究中，确定了细胞摄取甘露糖基化聚（乙二醇）-缀合物型NC的最佳结构构型。合成一系列NC以系统地评价甘露糖单元（Man）的数目、PEG载体大小和相邻甘露糖单元之间的mPEG间隔基长度对NC摄取到表达MR的J774.E鼠巨噬细胞样细胞中的影响。在具有0、1、2或4个甘露糖单位的NC中，（Man）2-NC的摄取是最高的，这表明在空间上阻碍内吞作用的细胞表面上的亲合力和NC-MR簇集之间的权衡。将该最佳（Man）2-NC构型构建到后续NC中以优化其他两个参数，PEG载体大小和间隔区长度。具有0、5、12、20、30或40 kDa线性PEG载体的NC显示PEG大小与摄取之间的反比关系。选择12 kDa PEG载体用于研究第三个参数，人-人距离，因为它可以代表最佳权衡（即，组织穿透对全身清除）用于体内巨噬细胞靶向。合成了三种具有不同Man-Man距离（39、56或89 kDa）的（Man）2-PEG 12 kDa NC。甘露糖之间距离为56 μ m的NC的摄取分别比距离为39 μ m和89 μ m的NC高4倍和2倍。共聚焦显微镜证实，具有56 μ mMan-Man距离的优化的（Man）2-PEG 12 kDa NC通过与温度依赖性主动摄取一致的内吞作用内化。总之，用于靶向巨噬细胞样J774.E细胞上的MR的最佳NC结构参数是（i）小PEG聚合物载体，（ii）每个NC两个甘露糖单元和（iii）相邻甘露糖单元之间的56 μ m距离。
Macrophages are involved in a number of diseases, such as HIV infection/AIDS, tuberculosis, tumor development and atherosclerosis. Macrophages possess several cell surface receptors (e.g., the mannose receptor, MR) that may serve as drug delivery cellular portals for nanocarriers (NCs). In this study, the optimal structural configuration for cell uptake of mannosylated poly(ethylene glycol)-conjugate type NCs was determined. A series NCs was synthesized to systematically evaluate the effects of the number of mannose units (Man), the PEG carrier size and the mPEG spacer length between adjacent mannose units on NC uptake into MR-expressing J774.E murine macrophage-like cells. Among NCs with 0, 1, 2 or 4 units of mannose, the uptake of (Man)2-NC was the highest, suggesting a trade-off between avidity and NC-MR clustering on the cell surface that sterically hinders endocytosis. This optimal (Man)2-NC configuration was built into subsequent NCs to optimize the other two parameters, PEG carrier size and spacer length. NCs with 0, 5, 12, 20, 30 or 40 kDa linear PEG carriers showed an inverse relationship between PEG size and uptake. The 12 kDa PEG carrier was chosen for investigating the third parameter, the Man-Man distance, since it may represent the best trade off (i.e., tissue penetration vs. systemic clearance) for in vivo macrophage targeting. Three (Man)2-PEG12kDa NCs with different Man-Man distances (39, 56 or 89 Å) were synthesized. The uptake of the NC with the 56 Å distance between mannoses was four- and two-fold higher than NCs with 39 Å and 89 Å distances, respectively. Confocal microscopy confirmed that the optimized (Man)2-PEG12kDa NC with the 56 Å Man-Man distance was internalized via endocytosis consistent with temperature-dependent active uptake. In conclusion, the optimal NC structural parameters for targeting the MR on macrophage-like J774.E cells are (i) a small PEG polymer carrier, (ii) two mannose units per NC and (iii) a 56 Å distance between adjacent mannose units.
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影响因子：
4.8
作者：
Feinberg, H;Park-Snyder, S;Weis, WI
通讯作者：
Weis, WI
DOI：
10.1073/pnas.74.11.5031
发表时间：
1977-01-01
影响因子：
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作者：
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影响因子：
3.8
作者：
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