title: Development of a therapeutic model of precancerous liver using crocin-coated magnetite nanoparticles.
abstract: 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.
authors.affiliation: Department of Biology, College of Science, UAE University, Al-Ain, United Arab Emirates.
authors.forename: Rkia
authors.initials: R
authors.lastname: El-Kharrag
authors.affiliation: Department of Biology, College of Science, UAE University, Al-Ain, United Arab Emirates.
authors.forename: Amr
authors.initials: A
authors.lastname: Amin
authors.affiliation: Department of Chemistry, College of Science, UAE University, Al-Ain, United Arab Emirates.
authors.forename: Soleiman
authors.initials: S
authors.lastname: Hisaindee
authors.affiliation: Department of Chemistry, College of Science, UAE University, Al-Ain, United Arab Emirates.
authors.forename: Yaser
authors.initials: Y
authors.lastname: Greish
authors.affiliation: Department of Anatomy, College of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates.
authors.forename: Sherif M
authors.initials: SM
authors.lastname: Karam
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002338:Carotenoids / Q000008:administration & dosage* / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity; D016503:Drug Delivery Systems; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D058185:Magnetite Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D058185:Magnetite Nanoparticles; D002338:Carotenoids; D004052:Diethylnitrosamine; C029036:crocin