Multivalent Targeting of the Asialoglycoprotein Receptor by Virus-Like Particles.
Multivalent Targeting of the Asialoglycoprotein Receptor by Virus-Like Particles.
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DOI：
10.1002/smll.202304263
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发表时间：
2023-08
期刊：
影响因子：
13.3
通讯作者：
Robert Hincapie;S. Bhattacharya;M. Baksh;Carlos A. Sanhueza;Elisa Schrader Echeverri;H. Kim;Kalina Paunovska;A. R. Podilapu;Minghao Xu;J. Dahlman;M. Finn
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文献类型：
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作者：
Robert Hincapie;S. Bhattacharya;M. Baksh;Carlos A. Sanhueza;Elisa Schrader Echeverri;H. Kim;Kalina Paunovska;A. R. Podilapu;Minghao Xu;J. Dahlman;M. Finn
脱唾液酸糖蛋白受体（ASGPR）在肝细胞上高密度表达。半乳糖基碳水化合物的多价变体以高亲和力结合 ASGPR，从而能够将配体结合的货物输送到肝脏。相对高亲和力配体的病毒样颗粒 (VLP) 缀合物被表达 ASGPR 的细胞有效内吞，其方式强烈依赖于配体展示的性质和密度，最佳配方使用纳摩尔水平的粘合剂，而不是皮摩尔水平的粘合剂。与竞争性小分子或天然多半乳糖基化配体脱唾液酸类粘蛋白相比，优化的颗粒被 HepG2 细胞吸收的效率更高。在小鼠全身注射后，这些 VLP 迅速被肝脏清除，并被发现与肝窦内皮细胞、库普弗细胞、肝细胞、树突状细胞和其他免疫细胞相关。 ASGPR 靶向和非靶向颗粒的分布与内皮细胞和库普弗细胞相似，但靶向颗粒分布到更多数量和部分的肝细胞。因此，肝脏中的选择性细胞运输很难实现：即使使用最有效的 ASGPR 靶向，屏障细胞也会吸收大部分注射的颗粒，并且在最佳情况下，肝细胞的访问效率仅为大约两倍。
The asialoglycoprotein receptor (ASGPR) is expressed in high density on hepatocytes. Multivalent variants of galactosyl carbohydrates bind ASGPR with high affinity, enabling hepatic delivery of ligand-bound cargo. Virus-like particle (VLP) conjugates of a relatively high-affinity ligand were efficiently endocytosed by ASGPR-expressing cells in a manner strongly dependent on the nature and density of ligand display, with the best formulation using a nanomolar-, but not a picomolar-level, binder. Optimized particles were taken up by HepG2 cells with greater efficiency than competing small molecules or the natural multigalactosylated ligand, asialoorosomucoid. Upon systemic injection in mice, these VLPs were rapidly cleared to the liver and were found in association with sinusoidal endothelial cells, Kupffer cells, hepatocytes, dendritic cells, and other immune cells. Both ASGPR-targeted and nontargeted particles were distributed similarly to endothelial and Kupffer cells, but targeted particles were distributed to a greater number and fraction of hepatocytes. Thus, selective cellular trafficking in the liver is difficult to achieve: even with the most potent ASGPR targeting available, barrier cells take up much of the injected particles and hepatocytes are accessed only approximately twice as efficiently in the best case.