Abstract
Selective targeting of anticancer drugs to the tumor site is beneficial in the pharmacotherapy of hepatocellular carcinoma (HCC). This study evaluated the prospective of galactosylated chitosan nanoparticles as a liver-specific carrier to improve the therapeutic efficacy of gemcitabine in HCC by targeting asialoglycoprotein receptors expressed on hepatocytes. Nanoparticles were formulated (G1–G5) by an ionic gelation method and evaluated for various physicochemical characteristics. Targeting efficacy of formulation G4 was evaluated in rats. Physicochemical characteristics exhibited by nanoparticles were optimal for administering and targeting gemcitabine effectively to the liver. The biphasic release behavior observed with G4 can provide higher drug concentration and extend the pharmacotherapy in the liver target site. Rapid plasma clearance of gemcitabine (70% in 30 min) from G4 was noticed in rats with HCC as compared to pure drug (p < 0.05). Higher uptake of gemcitabine predominantly by HCC (64% of administered dose; p < 0.0001) demonstrated excellent liver targeting by G4, while mitigating systemic toxicity. Morphological, biochemical, and histopathological examination as well as blood levels of the tumor marker, alpha-fetoprotein, in rats confirmed the curative effect of G4. In conclusion, this study demonstrated site-specific delivery and enhanced in vivo anti-HCC efficacy of gemcitabine by G4, which could function as promising carrier in hepatoma.
Highlights
Hepatocellular carcinoma (HCC) is one of the predominant forms of liver cancer and accounts approximately for 90% of total hepatic malignancy
The amide bond formation between the primary amine group of chitosan and carboxyl group of lactobionic acid was carried out using 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide and N-hydroxylsuccinimide, which are widely used as chemical cross linking agents
Fouriertransform transform infrared (FTIR) studies confirmed the absence of drug–polymer interaction, and Differential scanning calorimetry (DSC) thermograms indicate the amorphous state of gemcitabine present in the nanoparticles
Summary
Hepatocellular carcinoma (HCC) is one of the predominant forms of liver cancer and accounts approximately for 90% of total hepatic malignancy. Conventional chemotherapy is less effective in treating HCC essentially due to the poor specificity of these agents to malignant tumor cells. Current therapeutic strategies in HCC aim to improve the clinical potential of chemotherapeutic agents by targeting them to the tumor site [3]. The active targeting of anticancer drugs by developing carrier systems with specific ligands has attained much attention [5]. These nano-sized ligand-bound systems will potentially transport the drug to the tumor site and bind effectively to the overexpressed target receptors in cancer cells. Lipid-based formulations such as liposomes, micelles, and emulsions with diverse ligand moieties to target liver cells have been developed [8]. The pharmacological and therapeutic responses are improved when these carriers are combined with ligands [5,11]
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