Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor.
Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor.
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DOI：
10.1021/jacs.6b12964
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发表时间：
2017-03-08
影响因子：
15
通讯作者：
Mascitti V
中科院分区：
文献类型：
--
作者：
Sanhueza CA;Baksh MM;Thuma B;Roy MD;Dutta S;Préville C;Chrunyk BA;Beaumont K;Dullea R;Ammirati M;Liu S;Gebhard D;Finley JE;Salatto CT;King-Ahmad A;Stock I;Atkinson K;Reidich B;Lin W;Kumar R;Tu M;Menhaji-Klotz E;Price DA;Liras S;Finn MG;Mascitti V
一个紧凑的和稳定的双环桥缩酮被开发作为去唾液酸糖蛋白受体（ASGPR）的配体。该化合物显示出优异的配体效率，并且通过配体结合的ASGPR的第一X射线晶体结构揭示了结合的分子细节。该类似物用于制备ASGPR的有效二价和三价结合剂。这些化合物的功能的广泛表征显示了体外快速的ASGPR依赖性细胞摄取和体内高水平的肝脏/血浆选择性。原型Alexa 647标记的三价缀合物在啮齿动物中的生物分布评估显示选择性肝细胞靶向，在非实质细胞中没有可检测的分布。与类似的GalNAc衍生的三聚体缀合物相比，该分子还表现出增加的ASGPR定向的肝细胞摄取和延长的保留。被动渗透性小分子货物在肝脏中的选择性释放是通过氧杂降冰片二烯键的逆狄尔斯-桤木裂解实现的，推测是在遇到细胞内硫醇时。因此，本文所述的多组分构建体代表了向肝细胞的高效递送载体。
A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels–Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes.
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