Development of a therapeutic model of precancerous liver using crocin-coated magnetite nanoparticles

• Published in: International journal of oncology Vol. 50; no. 1; pp. 212 - 222
• Main Authors: El-Kharrag, Rkia, Amin, Amr, Hisaindee, Soleiman, Greish, Yaser, Karam, Sherif M
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.01.2017; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Animals; Apoptosis; Biomarkers; Cancer therapies; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Care and treatment; Carotenoids; Carotenoids - administration & dosage; Carotenoids - chemistry; Cell Proliferation - drug effects; Chemotherapy; crocin; Development and progression; Diethylnitrosamine - toxicity; Drug Delivery Systems; Fourier transforms; Health aspects; Hep G2 Cells; Hepatoma; Humans; Liver cancer; Liver Neoplasms - chemically induced; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Magnetite; magnetite nanoparticles; Magnetite Nanoparticles - administration & dosage; Magnetite Nanoparticles - chemistry; Mice; Nanoparticles; Neoplasms, Experimental - chemically induced; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Oxidative Stress - drug effects; precancerous liver; Rodents; saffron; Spectrum analysis
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2016.3769

Despite considerable advances in understanding hepatocellular carcinoma, it is one of the common and deadliest cancers worldwide. Hence, increasing efforts are needed for early diagnosis and effective treatments. Saffron has been recently found to inhibit growth of liver cancer in rats. The aim of this study was to develop an effective method for treatment of liver cancer using magnetite nanoparticles (MNPs) coated with crocin, the main active component of saffron. MNPs were prepared and initially coated with dextran and a cross-linker to enhance conjugation of crocin using a modified coprecipitation method. Cultured HepG2 cells and diethylnitrosamine-injected mice were treated with corcin-coated MNPs and analyzed using cell proliferation assay and immunohistochemical analysis, respectively. Treatment of HepG2 cells with crocin-coated MNPs led to a significant inhibition of their growth as compared to control or those treated with free crocin or uncoated MNPs. Histological examinations of the livers of diethylnitrosamine-injected mice revealed several precancerous changes: multiple proliferative hepatic foci, hyper- or dysplastic transformations of bile ducts/ductules, and nuclear atypia associated with polyploidy, karyomegaly, and vacuolation. Immunohistochemistry using antibodies specific for cell proliferation (Ki-67) and apoptosis (M30-CytoDEATH and Bcl-2) revealed their upregulation during development of precancerous lesions. Using antibodies specific for inflammation (cyclooxygenase-2), oxidative stress (glutathione) and angiogenesis (vascular endothelial growth factor) indicated the involvement of multiple signaling pathways in the development of precancerous lesions. Treatment with crocin-coated MNPs was associated with regression of precancerous lesions, significant upregulation of apoptotic cells and downregulation of Bcl-2 labeling and markers of cell proliferation, inflammation, oxidative stress and angiogenesis. In conclusion, crocin-coated MNPs are more effective than free corcin for treatment of liver precancerous lesions in mice. These findings will help to develop new modalities for early detection and treatment of liver precancerous lesions.