Differential receptor targeting of liver cells using 99mTc-neoglycosylated human serum albumins

Abstract

Neolactosyl human serum albumin (LSA) targets asialoglycoprotein receptor and shows high liver uptake due to accumulation in hepatocytes. Although neomannosyl human serum albumin (MSA) also shows high liver uptake, it has been reported to be taken up by Kupffer cells and endothelial cells. We compared the biological properties of LSA and MSA. 99mTc-LSA and 99mTc-MSA biodistribution in mice were investigated after intravenous injection. In vivo localization of rhodaminisothiocyanate (RITC)-LSA and fluoresceineisothiocyanate (FITC)-MSA were investigated in mouse liver. Excretion routes of 99mTc-LSA and 99mTc-MSA metabolites were examined. Both 99mTc-LSA and 99mTc-MSA showed high liver uptakes. RITC-LSA was taken up by hepatocytes whereas FITC-MSA was taken up by Kupffer cells and endothelial cells. 99mTc-MSA showed higher spleen and kidney uptakes than 99mTc-LSA. 99mTc-LSA metabolites excreted in urine and feces accounted for 44.4 and 50.0% of 99mTc-LSA injected, respectively, while 99mTc-MSA metabolites accounted for 51.5 and 10.3%, respectively. In conclusion, LSA is specifically taken up by hepatcytes while MSA by Kupffer cells and endothelial cells. After taken up by the liver, LSA is metabolized by the hepatocytes and then excreted through both the hepatobiliary tract and kidney, whereas MSA is metabolized by Kupffer cells and endoghelial cells and then excreted mainly through the kidney.

Nanoparticles Modified by Encapsulation of Ligands with a Long Alkyl Chain to Affect Multispecific and Multimodal Imaging

“…Mannose receptor is known to exist on the surfaces of macrophages, and thus, mannosylated human serum albumin is used to target bone marrow and liver, especially Kupffer cells. On the other hand, lactosylated human serum albumin is used for liver imaging because it binds to asialoglycoprotein receptors on hepatocytes (32,38). This experiment also proved specific uptake of the encapsulated QDs, representing the feasibility of wide application of the agents.…”

“…RGD derivatives have been used to investigate a v b 3 integrin expression in vascular and tumor angiogenesis by biologic and clinical researchers (24)(25)(26)(27)(28)(29). In addition, a mannose and stearylamine conjugate (Man-C 18 ) was synthesized to target the mannose receptor of Kupffer cells (30)(31)(32)(33), and a lactose and stearylamine conjugate (Lac-C 18 ) was synthesized to target the asialoglycoprotein receptor in the liver (32,34,35). For radiolabeling with 68 Ga, we conjugated the bifunctional chelating agent SCN-Bz-NOTA to stearylamine (NOTA-C 18 ).…”

Drug Delivery Systems and Liver Targeting for the Improved Pharmacotherapy of the Hepatitis B Virus (HBV) Infection

“…Since targeting to the liver does not necessarily imply hepatocyte targeting, as Kupffer cells display phagocytosis capability (83,84), fine tuning the chemical modification of the carriers might be required to improve the accumulation in one cell type over the other. Moreover, accumulation in liver parenchyma does not imply that the prodrug is converted into the active agent.…”

Novel PET Imaging of Atherosclerosis with 68Ga-Labeled NOTA-Neomannosylated Human Serum Albumin

“…Methods previously described in the literature were used to synthesize MSA from human serum albumin (13,19), RITC-MSA (15), and NOTA-MSA for 68 Ga labeling (17). The labeling efficiency and radiochemical purity determined by instant thin-layer chromatography silica gel were always greater than 98%.…”

“…When intravenously injected into rats, mannosylated bovine serum albumin rapidly binds to the Kupffer and endothelial cells in the liver because of the presence of MRs on these cells (14,15). MSA is synthesized by conjugating a-D-mannopyranosylphenyl isothiocyanate (SCN-mannose) with human serum albumin.…”