Liver cancer takes fifth place in the rating of most common types among men and the eighth among women worldwide. The most common type of liver cancer is hepatocellular carcinoma (HCC) - more than 75% of liver cancer is HCC¹. Now, to treat this type of cancer oncologists are using cytotoxic drugs which also affect healthy tissues.
The main goal of the work was to study targeted delivery to the liver. So the focus was to find the most promising target cells and drug molecules. In this work, the asialoglycoprotein receptor was chosen as the delivery site, which is the best option for targeted delivery of drugs to the liver due to its location on the surface of hepatocytes. As targeting molecules native ligands of ASGPR were used. We chose modified triterpenic and bile acids as medical molecules. In their unmodified state they show anticancer and anti-inflammatory properties. Studies were held to obtain ligands’ dissociation constants to determine which of them have the potential to be used in therapy. Spectroscopy of surface plasmon resonance was used to study the parameters of interaction of ASGPR with various ligands.
Multivalent ligands were demonstrating a cooperative effect. Dissociation constant decreases with increasing amount of N-acetylgalactosamine (GalNAc) residues: K_D = 19,6 ± 9,8 nM(mono-), K_D = 1,3 ± 1,1 nM(bi-), K_D = 0,7 ± 0,2 nM(three-). The length of the linker between the skeleton of the molecule and the residue of GalNAc had an impact on the obtained dissociation constant. This is presumably due to an increase in the mobility of GalNAc: K_D = 0,8 ± 0,1 nM for long linker and K_D = 19,5 ± 9,8 nM for the long one. The effect of the presence of hydroxyl groups in the skeleton of bile acid on binding to the receptor also had an impact on the obtained dissociation constant. We assume that this is due to a change in the hydrophobicity of the ligand. Steric factors on nonspecific binding of triterpenic acids to the hydrophobic site of ASGPR influenced obtained data. This can mean that some form of non-specific binding is taking place when ASGPR reacts with ligands.
Few of studied ligands with the obtained values of the dissociation constant less than 1 nM can be considered as leading compounds for the further development of a platform for targeted drug delivery to hepatocytes.