الفهرس 
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Abstract
Hepatocellular carcinoma (HCC), the most frequently diagnosed malignancy in liver, is the third largest cause for cancer-related death in the world, with more thanone million deaths annually. More than 80% of the patients present with advanced or unresectable disease, and the patients accepting resections experienced the recurrence rate of HCC as high as 50% in 2 years .
So, the systemic chemotherapy is especially demanded.
However, conventional chemotherapy for HCC suffers some limitations; (a) Limited aqueous solubility which requires solvents to formulate the dosage form which contribute to severe toxicity, (b) Lack of selectivity of anticancer drugs causing significant damage to rapidly proliferating normal cells and (c) Multidrug resistance mainly due to increased efflux pumps such as P-glycoprotein (Pgp) in the cell membrane which are responsible for transport of various anticancer drugs out of cells.
Therefore, the development of an effective hepatocellular carcinoma targeteddrug delivery system is extremely important to improve the drug efficacy to hepatic cancer cells, and reduce toxic side effects systematically.
For several diseases hepatocytes represent the most relevant target cell. Hepatocytes play a crucial role in liver diseases like viral hepatitis and HCC. In all these cases, hepatocytes are infected ordamaged and as a consequence they initiate the disease activity. Drug uptake by this particular cell-type is in general not a major issue due to the first pass effect and the presence of many transporters and endocytotic receptors that take up drugs.
Nevertheless, to enhance the therapeutic effects (in case of hepatocellular carcinoma, viral hepatitis and in case of gene-based therapies) or to reduce side-effects of drugs (in case of for instance antiviral or anticancer drugs) many methods for hepatocyte-selective drug targeting have been explored in the past decades. In most cases, the asialoglycoprotein receptor (ASGP-R) has been used as the target receptor for drugdelivery to the hepatocyte. Galactose residues or lactose moieties have been coupled to proteins, polymers or incorporated into the outer layer of liposomes.
The asialoglycoprotein receptor is specifically and abundantly present on hepatocytes and this receptor has been used to deliver all kinds of therapeutic compounds ranging from therapeuticproteins, antiviral agents to anticancer drugs into hepatocytes.
Nanoparticles derived from natural proteins are biodegradable, metabolizable, and are easily amenable to surface modifications to allow attachment of drugs and targeting ligands. They have been successfully synthesized from various proteins includingwater-soluble proteins (e.g., bovine and human serum albumin) and insoluble proteins (e.g., zein, caseinand gliadin).
This study focuses on the development of two different protein-basedNPs, gliadin nanoparticles and casein micelles for the co-delivery of two different drug combinations.
The NPs are administrated to HCC induced mice and antitumor efficacy was evaluated by measuring tumor markers expression levels and histopathological changes.