Galactosylated hydroxyl‐polyamidoamine dendrimer targets hepatocytes and improves therapeutic outcomes in a severe model of acetaminophen poisoning‐induced liver failure

Abstract

Toxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose‐conjugated hydroxyl polyamidoamine dendrimer (D4‐Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)‐induced liver failure. D4‐Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non‐Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4‐Gal conjugated to N‐acetyl cysteine (NAC) was tested in a mouse model of APAP‐induced liver failure. A single intravenous dose of a conjugate of D4‐Gal and NAC (Gal‐D‐NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4‐Gal is effective in targeting and delivering therapies to hepatocytes and Gal‐D‐NAC has the potential to salvage and treat liver injury with a broader therapeutic window.

Advances in the study of acetaminophen-induced liver injury

“…The results showed that Gal-D-NAC could reduce cellular oxidative stress and shrink hepatocyte necrotic areas, thus improving the survival rate of AILI mice. Specifically, the effectiveness persisted when Gal-D-NAC was administered 8 h after excessive APAP exposure (Porterfield et al, 2023).…”

“…It has a high affinity for galactose, lactose, and glucose (Bon et al, 2017). Porterfield et al (2023) synthesized a polymer named D4-Gal, which binds to ASGPR and selectively targets hepatocytes in healthy mice and AILI mouse models. They further synthesized Gal-D-NAC, a D4-Gal conjugate containing NAC, and tested it in the above model.…”

Recent Advances in Nanomaterials-Based Targeted Drug Delivery for Preclinical Cancer Diagnosis and Therapeutics

“…Due to their polyvalent property, dendrimers are capable of attaching several imaging probes and hence can serve as an excellent tool for the cancer diagnosis. Recently, DNA-assembled polyamidoamine dendritic clusters have shown encouraging results in the specific targeting of cancer cells [45,46]. Furthermore, the photothermal and photodynamic treatment efficacy of photosensitizerdecorated confeito-like gold nanoparticles for cancer therapy has been demonstrated to be enhanced by nanoscaled polyamidoamine dendrimer spacer [47].…”

Dendrimers in Corneal Drug Delivery: Recent Developments and Translational Opportunities

“…Due to their unique properties as biocompatible nanomaterials, research in dendrimers has seen a recent boom in popularity to solve modern challenges in drug delivery [ 49 , 96 , 97 , 98 , 99 , 100 ]. The first successful example of a dendrimer-based product is VivaGel ® , developed by Australia-based company Starpharma.…”