Doxorubicin coupled to lactosaminated albumin inhibits the growth of hepatocellular carcinomas induced in rats by diethylnitrosamine

Prodrug Strategies in Anticancer Chemotherapy

“…[70,71] This receptor has a high affinity for terminal b-galactoside and b-N-acetylgalactosamine residues on glycoproteins [72,73] and is responsible for the endocytosis of several glycoproteins. [40,74,75] The strong interaction of glycoproteins with the ASGPR is due to the "cluster-glycoside effect" [76] in which adjacent saccharide groups (multivalent ligands or so-called glycoside clusters) are responsible for high binding constants.…”

“…[272][273][274] In an- other approach, the (6-maleimidocaproyl)hydrazone derivative of doxorubicin was coupled to a thiolated form of lactosaminated human albumin (L-HSA) ( Figure 26). [70,82,275] The resulting conjugate L-HSA-DOXO achieved very efficient targeting of the drug to the livers of treated mice, with doxorubicin concentrations reaching levels 7-20-fold higher than those raised in extrahepatic tissues. [275] In further experiments against hepatocellular carcinoma induced in rats by N,N-diethylnitrosamine, L-HSA-DOXO, at a dose of 4 1 mg kg À1 significantly inhibited tumor growth without decreasing body weight ( Figure 27).…”

“…In contrast, free doxorubicin administered at the same dose as the coupled drug did not affect tumor growth, and produced a significant decrease in the body weight of the treated animals. [70] Experiments in healthy rats have shown that even a dose of 4 2 mgkg À1 L-HSA-DOXO, twice that used in the therapeutic model, produces essentially no liver toxicity, indicating an excellent therapeutic index for the novel conjugate, [82] which is currently being developed for evaluation in a phase I trial. PK2 has been investigated in a phase I clinical trial, with two partial remissions and one minor response noted but it is not undergoing further clinical assessment.…”

Galactosylated polymeric carriers for liver targeting of sorafenib

“…Galactosylation is a speculated strategy in this field because targeting via galactosylated carriers exploit highly specific interactions of galactose ligands with endogenous lectin receptors such as asialoglycoprotein receptor (ASGPR), which is specifically and abundantly present on hepatocytes (Jain et al, 2012;Rensen et al, 2001;Wu et al, 2004). This receptor has been used to deliver to hepatocytes all kinds of therapeutic compounds ranging from therapeutic proteins, antiviral agents (Di Stefano et al, 1997) to anticancer drugs (Di Stefano et al, 2006;Fiume et al, 2005). Active targeting by coupling galactose (GAL) residues or lactose moieties to proteins and polymers or by their introduction on the colloidal surface of nanoparticles or polymeric micelles, allow enhancing the uptake of drug-loaded systems into hepatocytes with high degree of selectivity (Fiume and Di Stefano, 2010;Li et al, 2010;Poelstra et al, 2012;Suo et al, 2010;Suriano et al, 2010;Wu et al, 2010;Yang et al, 2011;Zheng et al, 2011).…”

Priority of Alpha-L- Fucosidase Over Alpha fetoprotein in Early Detection of Hepatocellular Carcinoma in Animals and Human

“…They received diethylnitrosamine (DENA) in drinking water (100 mg/l, (16). DENA solution was kept in dark bottles since the molecule is light-sensitive and was prepared fresh every week.…”