Targeted delivery of atorvastatin via asialoglycoprotein receptor (ASGPR)

Abstract

Targeted drug delivery platforms can increase the concentration of drugs in specific cell populations, reduce adverse effects, and hence improve the therapeutic effect of drugs. Herein, we designed two conjugates by installing the targeting ligand GalNAc (N-acetylgalactosamine) onto atorvastatin (AT). Compared to the parent drug, these two conjugates, termed G2-AT and G2-K-AT, showed increased hepatic cellular uptake. Moreover, both conjugates were able to release atorvastatin, and consequently showed dramatic inhibition of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase and increased LDL receptors on cell surface.

Design and synthesis of atorvastatin derivatives with enhanced water solubility, hepatoselectivity and stability

“…Previous studies reported that atorvastatin esters were not able to cause a biological effect until free atorvastatin was released. 13,21 Nevertheless, in our case esters 1b and 2a demonstrated slight inhibition of the HMG-CoA reductase (Fig. 2).…”

“…Atorvastatin conjugates underwent a two-step hydrolysis process that includes lactone formation as was demonstrated by the previous report. 13 Therefore, the linearity of the atorvastatin release corresponds to the pseudo zero-order intramolecular deesterification.…”

“…Therefore, in this work the ligands were obtained using the earlier elaborated techniques. While compound A had already been applied by Y. Dong and coworkers to prepare atorvastatin conjugates, 13 azide B was used for this purpose for the first time. Taking into consideration that galactosyl analogues with diverse substituents at the anomeric position exhibit different affinities for the ASGPR, 17 the change from ligand A to ligand B may lead to increased binding to the receptor, as it was observed in the case of paclitaxel conjugates.…”

“…12 To date, there is only one publication describing statin prodrugs with an ASGPR ligand. 13 The two conjugates 1a and 2a (Fig. 1) reported in the article were designed as improved modifications of atorvastatin, the best-seller drug yet with low water solubility and bioavailability.…”

In vitro and in vivo antitumor effects of lupeol-loaded galactosylated liposomes

“…Sialic acid glycoprotein receptor (ASGPR) is a promising drug target for the HCC treatment because of its high expression on the surface of HCC cell line (Poelstra et al., 2012 ; Nair et al., 2019 ; Zhang et al., 2019 ). Also, lactoferrin (LF) and ASGPR can bind in a non-dependent way with high affinity.…”