Development of a Therapeutic Model of Early Liver Cancer Using Crocin-Coated

Rkia El-kharrag

Abstract

Hepatocellular carcinoma is one of the most common health problem that is difficult to treat. As a result of the side effects frequently experienced with conventional cancer treatments, there has been a growing interest to develop controlled drug delivery system that can reduce the mortality rate of liver cancer patients and unharmed healthy tissues. Magnetic nanoparticles are potentially important in hepatocellular carcinoma treatment, since they can be used as delivery system. Pure and coated magnetic nanoparticles were synthesized via modified co-precipitation method in air at low temperature. Various reaction parameters and coating materials have been investigated and characterized. Among these parameters and coating materials, 1.0% dextran was selected as an optimum coating for nanoparticles using a slow feeding rate for the Fe^2+/Fe³⁺ reactants, maintaining the stirring and soaking temperatures at 60°C. After that dextran-coated magnetic nanoparticles were bound to crocin, a pharmacologically active component of saffron, via cross linker. Crocin alone has shown anti-cancer activity in different in vitro and in vivo settings by several studies. The aim of this study was to synthesize the dextran-coated magnetite nanoparticles containing crocin with a higher therapeutic index for hepatocellular carcinoma treatment. The nanoparticles with crocin were tested in vitro and in vivo for their anti-cancer effects as compared to free crocin. HepG2 cells treated with crocin-dextran coated magnetite nanoparticles showed a decrease in cell proliferation compared to control (non-treated cell) or to those treated with free crocin or dextran-coated nanoparticles. The anti-cancer activity of crocin-dextran-coated nanoparticles was also evaluated in Balb/c mice. These mice were injected with carcinogenic agent, diethylnitrosamine, Histological examination revealed several precancerous changes. The immunohistochemical analysis using antibodies indication of cell proliferation (Ki-67), apoptosis (M30-Cytodeath and Bcl-2), inflammation (cyclooxygenase-2) and angiogenesis (vascular endothelial growth factor), indicated that magnetite nanoparticles conjugated with dextran plus crocin does indeed increase its anti-tumorigenic activity over free crocin. These results provided the basis for designing new modalities for treatment of liver cancer which could hopefully reduce its high mortality rate.