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Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth. VPA also induced down-regulation of Notch signaling via suppressing the expression of Notch1 and its target gene HES1, with an increase of tumor suppressor p21 and p63. Furthermore, Notch1 activation via overexpressing Notch1 active form ICN1 induced HCC cell proliferation and anti-apoptosis, indicating Notch signaling played an oncogenic role in HCC cells. Meanwhile, VPA could reverse Notch1-induced increase of cell proliferation. Interestingly, VPA was also observed to stimulate the expression of G protein-coupled somatostatin receptor type 2 (SSTR2) that has been used in receptor-targeting therapies. This discovery supports a combination therapy of VPA with the SSTR2-targeting agents. Our in vitro assay did show that the combination of VPA and the peptide-drug conjugate camptothecin-somatostatin (CPT-SST) displayed more potent anti-proliferative effects on HCC cells than did each alone. VPA may be a potential drug candidate in the development of anti-HCC drugs via targeting Notch signaling, especially in combination with receptor-targeting cytotoxic agents.

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A new method was developed to fabricate nanospheres and vesicles as drug carriers. The drug-loaded nanospheres and vesicles were prepared by self-assembly of alginate in aqueous media containing Ca 2+ and CO 3 2ions under very mild conditions. The preparation method did not involve any organic solvent and surfactant and could offer good control over the morphology and the size of self-assemblies. Through adjusting the preparation conditions, nanosized drug-delivery systems with different shapes, that is, nanospheres and vesicles, could be obtained. The morphologies of the drug-delivery systems were observed by transmission electron microscopy (TEM). 5-Fluorouracil (5-FU), an anticancer drug, was encapsulated in the nanospheres and vesicles, and in vitro drug release behavior was investigated. The effect of drug-loading content on the release was studied. The release of 5-FU could be effectively sustained from both drug-loaded nanospheres and vesicles because the presence of CaCO 3 in the nanospheres/vesicles could reduce the permeability of the entrapped drug for the alginate-based self-assemblies.

A novel strategy was developed to prepare nanospheres and vesicles as drug carriers. The drug-loaded pectin nanospheres and vesicles were fabricated in aqueous media containing Ca2+ and CO3(2-) ions under very mild conditions, which did not involve any surfactant. Through adjusting the preparation conditions, nanosized drug delivery systems with diverse morphologies, that is, nanospheres and vesicles, could be obtained. This technique could offer good control over the morphology and the size of nanospheres and vesicles. The morphologies of the aggregates were observed by environmental scanning electron microscopy and transmission electron microscopy. 5-Fluorouracil (5-FU), an antineoplastic drug, was encapsulated in the nanospheres and vesicles, and the in vitro drug release at different pH values was investigated. With the presence of Ca2+ and CO3(2-) ions in the pectin-based nanospheres/vesicles, the release of the low molecular weight drug could be effectively sustained from the highly hydrolyzed polysaccharide-based drug delivery systems.

The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.