الفهرس | Only 14 pages are availabe for public view |
Abstract Liver cancer is the most frequent and dangerous cancer worldwide. Some factors are leading to liver cancer like the bad habitats, HCV, HCB and excessive alcohol intakes. The liver cells are comprised majority of hepatocytes so, the most common liver cancer is hepatocellular carcinoma. There several treatments for hepatocellular carcinoma such as radiation, surgical removes, chemotherapies, transplantation.…etc. we concerned our study with chemotherapies especially cisplatin. However, the chemotherapies were circulating in the blood and cannot distinguish between non-tumor and tumor cells where it stops all the rapid growth cells like hair follicles, cells lining the stomach …. etc which may be normal or tumor cells. The severe side effects of all chemotherapies like hair loss, ulcers, mouth sores, loss of appetite, nausea and vomiting, diarrhea, increased chance of infections (from low white blood cell counts), easy bruising or bleeding (from low blood platelet counts), fatigue (from low red blood cell counts)…. etc. The most common anticancer therapeutic agent used in the treating of HCC is cisplatin (CDDP) where it is more effective and potent chemotherapy used in the treatment of multi types of tumor, such as cancer of the neck and head, melanoma, nonsmall cell of the cancer of lung, cervical cancer, liver cancer and nasopharyngeal carcinoma. The main side effect for cisplatin is acute kidney injury (AKI). Indeed, limiting clinical use of cisplatin due to its side effect. Although nephrotoxicity is a sever side effect with cisplatin therapy, the cisplatin was damaged selectively proximal tubule cells with unclear mechanism. To improve the efficacy and decrease the severe side effects of cisplatin, targeted drug delivery to selectively enter the tumor cells only, thus decreasing the chemotherapy concentration within non-tumor cells. So, in the present study we were entrapped cisplatin in a dual ligand vectors for selective reaching to the carcinoma part of liver tissues to decrease the side effect of cisplatin. So, to improve the efficacy of the therapy, we entrapped the drug in the hepatic targeted dual ligand drug transport way for treatmenting of liver malignancy, however the drug entered in a hepatic targeted vector is reached to the tumor cells only of liver through the specific sites between the cancer liver cells receptor and vector ligand, and drug that delivers to non-tumor liver tissue is decrease. The chitosan was extracted from the shrimp shells by using the chemical reagents. Chitosan is a linear polysaccharide polymer which has been widely used for drug delivery system, which was used in the forms of micro- and nanoparticles of chitosan, unique chitosan properties. So, it used in the formation of mucoadhesive compounds, increase the rate of dissolution specifically to hydrophobic substances, in the using of drug delivery, with enhancement of absorption of protein are the most frequent in the therapeutic applications of this polymer. Chitosan is a drug carrier which is a polysaccharide molecule like cellulose, which composed of 2 types of units which there are repeating from N-acetyl-d-glucosamine and dglucosamine, connected by (1-4)-β-glycosidic linkage. The -NH2 and -OH gps of chitosan which binded with glycyrrhetinic acid (GA) and galactose of lactobionic acid where the increase of selectivity targeting by entrance of either glycyrrhetinic acid or galactose subunits through these receptors. However, the amount and activity of the asialoglycoprotein receptor due to the presence of inhibitors in serum, where can decrease the capacity of the binding by 95% of primary HCC, are decrease through the pathogen conditions, where asialoglycoprotein receptor for selective transport is not effective alone. Glycyrrhetinic acid (GA) and galactose subunit of lactobionic acid reacted with glycyrrhetinic acid (GA) binding site and AGPR receptor, respectively. Our study was designed a novel vector GCGA and by 2 steps 1st one is formation of glycyrrhetinic acid binded with chitosan (GA-CTS) and 2nd one is formation of LA-modified GA-CTS (GCGA). Utilization of cisplatin complexed with alginate to prevent accumulation of platinum in the kidney so, decrease the nephrotoxicity with the same antitumor activity of cisplatin. where sodium alginate is a -ve polysaccharide glycosidically linked of L-guluronate and D-mannuronate residues and was extracted from marine algae. However, sodium alginate and chitosan were used in the drug delivery. Alginate was widely investigated as a drug delivery carrier. Due to the biodegradability and low toxicity of chitosan so, the presence of chitosan with alginate will increase the mechanical strength of alginate microparticles. The nanoparticles of cisplatin-alginate /GCGA formed by ionotropic gelation method via interaction between negatively carboxylic unit of alginate with the positively primary amine of chitosan (dual ligand modified chitosan GCGA) in the presence of Calcium chloride and tripolyphosphate as crosslinking reagents for chitosan and alginate respectively. In previous study, the results documented the potential effect of GCGA for delivery the drug to the cancer part of the liver. In this study we designed the cisplatin-alginate/GCGA nanoparticles which loaded with strongest chemotherapy, cisplatin for treating HCC in rats. |