Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor

• DOI: 10.1021/jacs.6b12964
• Publication Date: 2017-02-23T17:26:30Z
• Authors: Carlos A. Sanhueza; Michael M. Baksh; Benjamin Thuma; Marc D. Roy; Sanjay Dutta; Cathy Préville; Boris A. Chrunyk; Kevin Beaumont; Robert Dullea; Mark Ammirati; Shenping Liu; David Gebhard; James E. Finley; Christopher T. Sa...; Amanda King-Ahmad; Ingrid Stock; Karen Atkinson; Benjamin Reidich; Wen Lin; Rajesh Kumar; Meihua Tu; Elnaz Menhaji-Klotz; David A. Price; Spiros Liras; M. G. Finn; Vincent Mascitti
• Keywords: Asialoglycoprotein receptor; Conjugate; Biodistribution

A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent efficiency, molecular details of binding were revealed by first X-ray crystal structures ligand-bound ASGPR. analogue used to make potent di- trivalent binders Extensive characterization function these compounds rapid ASGPR-dependent cellular uptake in vitro high levels liver/plasma selectivity vivo. Assessment biodistribution rodents prototypical Alexa647-labeled conjugate selective hepatocyte targeting with no detectable distribution nonparenchymal cells. molecule also exhibited increased ASGPR-directed hepatocellular prolonged retention compared similar GalNAc derived trimer conjugate. Selective release liver passively permeable small-molecule cargo achieved retro-Diels-Alder cleavage an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, multicomponent construct described here represents highly efficient delivery vehicle hepatocytes.