• The Korean Journal of Nuclear Medicine
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• v.37 no.5
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• pp.301-307
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• 2003

Purpose: Lipiodol is used for targeting liver cancers by administrating through the hepatic artery. In the present study, feasibility of Re-188-sulfur colloid suspension in lipiodol as a liver cancer targeting agent was investigated. Materials and Methods: Re-188-sulfur colloid was prepared, harvested by centrifugation, washed with organic solvent and then suspended into lipiodol. Biodistribution of Re-188-sulfur colloid in normal saline and its suspension in lipiodol in mice after 1 hr of injection through the tail vein were investigated. Biodistribution and autoradiography of tumor-hearing liver was acquired after 5 min post-injection into left ventricle of the tumor-inoculated rats. Results: After 1 hr of injection with Re-188-sulfur colloid suspensiob in lipiodol through the tail vein in normal mice (n=3), the uptakes in the liver and lung were $5.2{\pm}0.7\;and\;91.0{\pm}1.7%$ ID/organ, respectively. After 5 min of injection with Re-188-sulfur colloid suspention in lipiodol through the left ventricle in the tumor-inoculated rats (n=4), uptakes in the normal liver, hepatoma, and lung were $0.41{\pm}0.28,\;1.88{\pm}1.57,\;and\;1.65{\pm}1.54%$ ID/organ, respectively. And autoradiography of hepatoma showed increased uptake than normal liver tissues. Conclusion: Re-188-sulfur colloid suspension in lipiodol injected through the artery shows higher uptake in the hepatoma than normal liver tissue that indicates the feasibility as a new radiopharmaceutical for therapy of hepatoma.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7441-7447
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• 2015

Objective: This study evaluated the safety and objective response of combining $^{131}I$-labeled-metuximab (Licartin) with transarterial chemoembolization (TACE) in the treatment of unresectable hepatocellular carcinoma (HCC). Materials and Methods: In a multicenter open-label clinical trial, 341 enrolled patients with stage III/IV HCC according to TNM criteria were nonrandomly assigned to a trial group (n=167) and a control group (n=174), undergoing TACE following hepatic intra-arterial injection of licartin or TACE alone from July 2007 to July 2009. Radiopharmaceutical distribution was evaluated. The primary endpoint was overall survival; secondary endpoints included time-to-progression (TTP), toxicity and adverse events (AEs). Results: The radiobiological distribution demonstrated better localization of licartin in liver tumors than other tissues (P<0.01). The organ absorbed doses to liver and red marrow were $3.19{\pm}1.01Gy$ and $0.55{\pm}0.22Gy$, respectively. The 1-year survival rate was significantly higher [79.47% vs. 65.59%, hazard ratio (HR), 0.598, P=0.041] and TTP significantly improved ($6.82{\pm}1.28$ vs. $4.7{\pm}1.14months$, P=0.037) compared with the control group. Patients at stage III achieved more benefit of one year survival than stage IV in the trial group (86.9% vs. 53.8%, P<0.001). There were significant different toxicities in leukocytopenia, thrombocytopenia and increased total bilirubin level [P<0.001, P=0.013, P<0.01, relative risk (RR) 1.63, 1.33, 1.43], but no differences in severe AEs of upper GI hemorrhage and severe liver dysfunction between the groups (5.39% vs. 2.3%, P=0.136). Conclusions: Owing to excellent tumor-targeting, promised efficacy and favourable toxicity profile, the novel combination therapy of licartin and TACE could be applied in patients with unresectable HCC.

• Journal of Microbiology and Biotechnology
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• v.16 no.9
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• pp.1369-1376
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• 2006

Self-organized nanogels were prepared from pullulan/biotin conjugates (PU/Bio) for the development of an effective anticancer drug delivery system. The degree of biotin substitution was 11, 19, and 24 biotin groups per 100 anhydroglucose units of pullulan. The physicochemical properties of the nanogels (PU/Bio1, 2 and 3) in aqueous media were characterized by dynamic light scattering, transmission electron microscopy, and fluorescence spectroscopy. The mean diameter of all the samples was less than 300 nm with a unimodal size distribution. The critical aggregation concentrations (CACs) of the nanoparticles in distilled water were $2.8{\times}10^{-2},\;1.6{\times}10^{-2}$, and $0.7{\times}10^{-2}mg/ml$ for the PU/Bio1, 2, and 3, respectively. The aggregation behavior of the nanogels indicated that biotin can perform as a hydrophobic moiety. To observe the specific interaction with a hepatic carcinoma cell line (HepG2), the conjugates were labeled with rhodamine B isothiocyanate (RITC) and their intensities measured using a fluorescence microplate reader. The HepG2 cells treated with the fluorescence-labeled PU/Bio nanoparticles were strongly luminated compared with the control (pullulan). Confocal laser microscopy also confirmed internalization of the PU/Bio nanogels into the cancer cells. Such results demonstrated that the biotin in the conjugate acted as both a hydrophobic moiety for self-assembly and a tumor-targeting moiety for specific interaction with tumor cells. Consequently, PU/Bio nanogels would appear to be a useful drug carrier for the treatment of liver cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.12
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• pp.4969-4976
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• 2014

Background: miR-152 is involved in the genesis and development of several malignancies. However, its role in HCC has not been fully clarified. The aim of this study was to investigate the clinicopathological significance of miR-152 and its effect on the malignant phenotype of HCC cells. Methods: miR-152 expression was detected using real-time quantitative RT-PCR in 89 pairs of HCC formalin-fixed paraffin-embedded and their adjacent tissues. Functionally, in vitro effects and mechanisms of action of miR-152 on proliferation, viability, caspase activity, apoptosis and motility were explored in HepG2, HepB3 and SNU449 cells, as assessed by spectrophotometry, fluorimetry, fluorescence microscopy, wound-healing and Western blotting, respectively. Results: miR-152 expression in HCC was downregulated remarkably compared to that in adjacent hepatic tissues. miR-152 levels in groups of advanced clinical stage, larger tumor size and positive HBV infection, were significantly lower than in other groups. A miR-152 mimic could suppress cell growth, inhibit cell motility and increase caspase activity and apoptosis in HCC cell lines. Furthermore, Western blotting showed that the miR-152 mimic downregulated Wnt-1, DNMT1, ERK1/2, AKT and TNFRS6B signaling. Intriguingly, inverse correlation of TNFRF6B and miR-152 expression was found in HCC and bioinformatics confirmed that TNFRF6B might be a target of miR-152. Conclusions: Underexpression of miR-152 plays a vital role in hepatocarcinogenesis and lack of miR-152 is related to the progression of HCC through deregulation of cell proliferation, motility and apoptosis. miR-152 may act as a tumor suppressor miRNA by also targeting TNFRSF6B and is therefore a potential candidate biomarker for HCC diagnosis, prognosis and molecular therapy.

• Journal of Life Science
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• v.34 no.4
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• pp.227-235
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• 2024

Hepatocyte damage caused by medications or herbal products is one of the important problem when these compounds are chronically administrated. Thus, improving hepatocyte survival during treatment offers a wide range of opportunities. Valproic acid (VPA), a branched short-chain fatty acid derived from naturally occurring valeric acid, is commonly used to treat epilepsy and seizures. Although VPA exerts numerous effects in cancer, HIV therapy, and neurodegenerative disease, its effects on the liver and its mechanism of action have not been fully elucidated. Here, we demonstrated that VPA caused moderate liver cell toxicity and apoptosis. Interestingly, VPA treatment increased transcription levels of PPAR alpha (PPAR-α) and fibroblast growth factor 21 (FGF21) in murine (Hepa1c1c7) hepatoma cells in a time and concentration dependent manner. VPA-induced FGF21 expression was significantly weaker under PPAR-α silencing condition than in cells transfected with non-targeting control siRNA. Subsequent experiments showed that cell viability was significantly lowered when the FGF21 signaling pathway was blocked by FGF receptor antagonist. Finally, we further determined that AMPK phosphorylation was not responsible for VPA-induced FGF21 expression and PPAR-a increments. These results indicate that increases of FGF21 expression alleviate VPA-induced hepatic toxicity, thereby making FGF21 a potential biomarker for predicting liver damage during VPA treatments.

• Journal of Life Science
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• v.31 no.8
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• pp.710-718
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• 2021

Placenta-derived mesenchymal stem cells (PD-MSCs) are promising candidates for cell-based therapy in regenerative medicine. The migration and homing potential of PD-MSCs to injured sites is a critical property of MSC engraftment. MicroRNAs (miRNAs) have recently been shown to regulate the critical functions of MSCs, such as proliferation, survival, and migration. The objective of the present study was to identify the miRNA and target genes involved in PD-MSCs homing in a bile duct ligation (BDL) rat model. We selected candidate miRNAs targeting genes for PD-MSCs homing based on microarray analysis. PD-MSC engraftment in BDL-injured rat liver was identified by immunofluorescence assay and human-specific Alu gene expression by quantitative real-time polymerase chain reaction (qRT-PCR) one week after transplantation. Compared with migrated naïve PD-MSCs under hypoxic and normoxic conditions (Hyp/Nor), the transplanted group with PD-MSCs (Tx) showed distinct differences in miRNA expressions in BDL-injured rat liver. We also validated the miRNAs and their target genes for PD-MSCs homing. The expressions of integrin α4 (ITGA4) and integrin α5 (ITGA5) target genes for miR-199a-5p and miR-148a-3p were significantly upregulated in the Tx group (p<0.05). In addition, integrin β1 (ITGB1) and integrin β8 (ITGB8) were upregulated by suppressing miR-183-5p and miR-145-5p, respectively. These results demonstrated that PD-MSCs regulate miRNA expression related to the integrin family for their homing effects on the BDL-injured rat liver. The findings further suggest that miRNA-mediated regulation of the integrin family contributes to the therapeutic efficacy of PD-MSCs in the rat hepatic fibrosis model by BDL.

• The Korean Journal of Nuclear Medicine
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• v.38 no.3
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• pp.253-258
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• 2004

Purpose: Chitosan has been studied as a non-viral gene delivery vector, drug delivery carrier, metal chelator, food additive, and radiopharmaceutical, among other things. Recently, galactose-graft chitosan was studied as a non-viral gene and drug delivery vector to target hepatocytes. The aim of this study was to investigate the usefulness of nuclear imaging for in vivo evaluation of targeting the hepatocyte by galactose grafting. Methods and Materials: Galactosyl methylated chitosan (GMC) was produced by methylation to lactobionic acid coupled chitosan. Cytotoxicity of $^{99m}Tc$-GMC was determined by MTT assay. Rabbits were injected via their auricular vein with $^{99m}Tc$-GMC and $^{99m}Tc$-methylated chitosan (MC), the latter of which does not contain a galactose group, and images were acquired with a gamma camera equipped with a parallel hole collimator. The composition of the galactose group in galactosylated chitosan (GC), as well as the tri-, di-, or mono-methylation of GMC, was confirmed by NMR spectroscopy. Results: The results of MTT assay indicated that $^{99m}Tc$-GMC was non-toxic. $^{99m}Tc$-GMC specifically accumulated in the liver within 10 minutes of injection and maintained high hepatic uptake. In contrast, $^{99m}Tc$-MC showed faint liver uptake. $^{99m}Tc$-GMC scintigraphy of rabbits showed that the galactose ligand principally targeted the liver while the chitosan functionalities led to excretion through the urinary system. Conclusion: Bioconjugation with a specific ligand endows some degree of targetability to an administered molecule or drug, as in the case of galactose for hepatocyte in vivo, and evaluating said targetabililty is a clear example of the great benefit proffered by nuclear imaging.