TY - JOUR
T1 - Rationally Designed Galactose Dendrimer for Hepatocyte-Specific Targeting and Intracellular Drug Delivery for the Treatment of Liver Disorders
AU - Sharma, Rishi
AU - Porterfield, Joshua E.
AU - An, Hyoung Tae
AU - Jimenez, Ambar Scarlet
AU - Lee, Seulki
AU - Kannan, Sujatha
AU - Sharma, Anjali
AU - Kannan, Rangaramanujam M.
N1 - Funding Information:
This study was partly funded by the NICHD grant number R01HD076901 (R.M.K.), NEI grant number RO1 EY025304 (R.M.K.), and NINDS grant number R01NS093416 (S.K.). A.S.J. was supported by the Johns Hopkins PREP grant (NIH R25GM109441). The authors wish to thank Kevin Liaw for assisting with intravenous injections. The authors also acknowledge the Wilmer core facility and imaging center (core grant: P30EY001765 and Research to Prevent Blindness) for confocal microscopy, cryosectioning and flow cytometry facilities.
Funding Information:
This study was partly funded by the NICHD grant number R01HD076901 (R.M.K.), NEI grant number RO1 EY025304 (R.M.K.), and NINDS grant number R01NS093416 (S.K.). A.S.J. was supported by the Johns Hopkins PREP grant (NIH R25GM109441). The authors wish to thank Kevin Liaw for assisting with intravenous injections. The authors also acknowledge the Wilmer core facility and imaging center (core grant: P30EY001765 and Research to Prevent Blindness) for confocal microscopy, cryosectioning, and flow cytometry facilities.
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/8/9
Y1 - 2021/8/9
N2 - Over two million people die of liver disorders every year globally. Hepatocytes are the key cells affected in several acute and chronic liver diseases. The current clinical outcomes of liver-targeted nanoparticles are limited, necessitating the need to develop smart hepatocyte-targeted drug delivery systems. Here, we present the rational design and development of a hepatocyte-targeting glycodendrimer (GAL-24) built from biocompatible building blocks, using expedite and facile chemical methodology. GAL-24 is designed to inherently target asialoglycoprotein receptor 1 (ASGP-R) on hepatocytes and shows significant accumulation in the liver (20% of injected dose), just 1 h after systemic administration. This is highly specific to hepatocytes, with over 80% of hepatocytes showing GAL-24-Cy5 signal at 24 h. GAL-24-Cy5 maintains hepatocyte-targeting capabilities in both a mouse model of severe acetaminophen poisoning-induced hepatic necrosis and a rat model of nonalcoholic steatohepatitis (NASH). This GAL-24 nanoplatform holds great promise for improved drug delivery to hepatocytes to combat many liver disorders.
AB - Over two million people die of liver disorders every year globally. Hepatocytes are the key cells affected in several acute and chronic liver diseases. The current clinical outcomes of liver-targeted nanoparticles are limited, necessitating the need to develop smart hepatocyte-targeted drug delivery systems. Here, we present the rational design and development of a hepatocyte-targeting glycodendrimer (GAL-24) built from biocompatible building blocks, using expedite and facile chemical methodology. GAL-24 is designed to inherently target asialoglycoprotein receptor 1 (ASGP-R) on hepatocytes and shows significant accumulation in the liver (20% of injected dose), just 1 h after systemic administration. This is highly specific to hepatocytes, with over 80% of hepatocytes showing GAL-24-Cy5 signal at 24 h. GAL-24-Cy5 maintains hepatocyte-targeting capabilities in both a mouse model of severe acetaminophen poisoning-induced hepatic necrosis and a rat model of nonalcoholic steatohepatitis (NASH). This GAL-24 nanoplatform holds great promise for improved drug delivery to hepatocytes to combat many liver disorders.
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U2 - 10.1021/acs.biomac.1c00649
DO - 10.1021/acs.biomac.1c00649
M3 - Article
C2 - 34324818
AN - SCOPUS:85112535746
VL - 22
SP - 3574
EP - 3589
JO - Biomacromolecules
JF - Biomacromolecules
SN - 1525-7797
IS - 8
ER -