Gene/Protein Disease Symptom Drug Enzyme Compound
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A new spectrophotometric method for quantitation of acetyl-CoA synthetase (ACAS) activity is developed. It has been applied for ACAS assay in the liver tissues of a woodchuck model of hepatitis virus-induced hepatocellular carcinoma (HCC). The assay is based on the established pyrophosphate (PPi) detection system. ACAS activity is indexed by the amount of PPi, the product of ACAS reaction system of activated form of acetate (acetyl-CoA) with ACAS catalysis. PPi is determined quantitatively as the amount of chromophore formed with molybdate reagent, 1-amino-2-naphthol-4-sulfonic acid in bisulfite and 2-mercaptoethanol. PPi reacts with molybdate reagent to produce phosphomolybdate and PPi-molybdate complexes. 2-mercaptoethanol is responsible for color formation which has the peak absorbance at 580 nm. This method was sensitive from 1 to 20 nmol of PPi in a 380-mul sample (1-cm cuvette). A ten-fold excess of Pi did not interfere with the determination of PPi. To study the major metabolic pathways of imaging tracer [1-(11)C]-acetate in tumors for detection of HCC by Positron Emission Tomography (PET), the activity of one of the key enzymes involved in acetate or [1-(11)C]-acetate metabolism, ACAS was assayed by this newly developed assay in the tissue samples of woodchuck HCCs. A significant increase of ACAS activity was observed in the liver tissues of woodchuck HCCs as compared with neighboring regions surrounding the tumors (P<0.05). The respective ACAS activities in the subcellular locations were also significantly higher in HCCs than in the surrounding tissues (P<0.05) (total soluble fraction: 876.61+/-34.64 vs. 361.62+/-49.97 mU/g tissue; cytoplasmic fraction: 1122.02+/-112.39 vs. 732.32+/-84.44 mU/g tissue; organelle content: 815.79+/-100.77 vs. 547.91+/-97.05 mU/ g tissue; sedimentable fragment: 251.92+/-51.56 vs. 90.94+/-18.98 mU/ g tissue). The finding suggests an increase in ACAS activity in the liver cancer of woodchuck models of HCC as compared to that in the normal woodchuck liver. The developed assay is rapid, simple and accurate and is suitable for the investigation of ACAS activity under physiologic and pathophysiologic conditions.
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PMID:A colorimetric assay method to measure acetyl-CoA synthetase activity: application to woodchuck model of hepatitis virus-induced hepatocellular carcinoma. 1739 95

A broad array of water-insoluble compounds has displayed therapeutically relevant properties toward a spectrum of medical and physiological disorders, including cancer and inflammation. However, the continued search for scalable, facile, and biocompatible routes toward mediating the dispersal of these compounds in water has limited their widespread application in medicine. Here we demonstrate a platform approach of water-dispersible, nanodiamond cluster-mediated interactions with several therapeutics to enhance their suspension in water with preserved functionality, thereby enabling novel treatment paradigms that were previously unrealized. These therapeutics include Purvalanol A, a highly promising compound for hepatocarcinoma (liver cancer) treatment, 4-hydroxytamoxifen (4-OHT), an emerging drug for the treatment of breast cancer, as well as dexamethasone, a clinically relevant anti-inflammatory that has addressed an entire spectrum of diseases that span complications from blood and brain cancers to rheumatic and renal disorders. Given the scalability of nanodiamond processing and functionalization, this novel approach serves as a facile, broadly impacting and significant route to translate water-insoluble compounds toward treatment-relevant scenarios.
ACS Nano 2009 Jul 28
PMID:Nanodiamond-mediated delivery of water-insoluble therapeutics. 1953 85

Gold nanocubes demonstrate unique optical properties of the high photoluminescence (PL) quantum yield and a remarkably enhanced extinction band at 544 nm. The 4 x 10(-2) PL yield, which is about 200 times higher than that of gold nanorods, allows gold nanocubes to be successfully used in cell imaging of human liver cancer cells (QGY) and human embryo kidney cells (293T) with a common method of single-photon excitation. The high extinction coefficients of gold nanocubes also facilitate them carrying out the photothermal therapy of QGY and 293T cells, showing similar photokilling efficiency as compared to gold nanorods.
ACS Nano 2010 Jan 26
PMID:High-photoluminescence-yield gold nanocubes: for cell imaging and photothermal therapy. 2001 23

Liver fibrosis or cirrhosis is one of the representative liver diseases with a high morbidity and mortality worldwide. Over the past decades, many kinds of antifibrotic compounds have been investigated in vitro and in vivo for the treatment of liver cirrhosis. In this work, real-time bioimaging of hyaluronic acid (HA) derivatives was carried out using quantum dots (QDots) to assess the possibility of HA derivatives as target-specific drug delivery carriers for the treatment of liver diseases. HA-QDot conjugates with an HA modification degree of about 22 mol % was synthesized by amide bond formation between carboxyl groups of QDots and amine groups of adipic acid dihydrazide modified HA (HA-ADH). According to in vitro cell culture tests, HA-QDot conjugates were taken up more to the cells causing chronic liver diseases such as hepatic stellate cells (HSC-T6) and hepatoma cells (HepG2) than normal hepatocytes (FL83B). After tail-vein injection, HA-QDot conjugates were target-specific, being delivered to the cirrhotic liver with a slow clearance longer than 8 days. Furthermore, immunofluorescence and flow cytometric analyses of dissected liver tissues revealed the target-specific delivery of HA derivatives to liver sinusoidal endothelial cells (LSEC) and HSC. The results were thought to reflect the feasibility of HA derivatives as novel drug delivery carriers for the treatment of various chronic liver diseases including hepatitis, liver cirrhosis, and liver cancer.
ACS Nano 2010 Jun 22
PMID:Bioimaging for targeted delivery of hyaluronic Acid derivatives to the livers in cirrhotic mice using quantum dots. 2051 53

Mesoporous silica nanomaterial is one of the most promising candidates as drug carrier for cancer therapy. Herein, in vitro and in vivo study of silica nanorattle (SN) with mesoporous and rattle-type structure as a drug delivery system was first reported. Hydrophobic antitumor drug docetaxel (Dtxl) was loaded into the PEGylated silica nanorattle (SN-PEG) with a diameter of 125 nm via electrostatic absorption. In human liver cancer cell Hep-G2, the half-maximum inhibiting concentration (IC(50)) of silica nanorattle encapsulated docetaxel (SN-PEG-Dtxl) was only 7% of that of free Dtxl at 72 h. In vivo toxicity assessment showed that both nanocarrier of silica nanorattle (40 mg/kg, single dose) and SN-PEG-Dtxl (20 mg/kg of Dtxl, three doses) had low systematic toxicity in healthy ICR mice. The SN-PEG-Dtxl (20 mg/kg, intravenously) showed greater antitumor activity with about 15% enhanced tumor inhibition rate compared with Taxotere on the marine hepatocarcinoma 22 subcutaneous model. The results prove that the SN-PEG-Dtxl has low toxicity and high therapy efficacy, which provides convincing evidence for the silica nanorattle as a promising candidate for a drug delivery system.
ACS Nano 2010 Nov 23
PMID:In vivo delivery of silica nanorattle encapsulated docetaxel for liver cancer therapy with low toxicity and high efficacy. 2097 87

A new core-shell nanostructure consisting of inorganic hydroxyapatite (HAP) nanoparticles as the core and organic alginate as the shell (denoted as HAP@Alg) was successfully synthesized by a pre-gel method and applied to pH-responsive drug delivery systems (DDS). HAP@Alg nanoparticles have the advantages of hydroxyapatite and alginate, where hydroxyapatite provides pH-responsive degradability, and alginate provides excellent biocompatibility and COOH functionality. Through the subsequent addition of CaCl(2) and phosphate solutions to the alginate solution, HAP@Alg nanoparticles with controllable particle sizes (ranging from 160 to 650 nm) were obtained, and their core-shell structure was confirmed through transmission electron microscopy (TEM) observation. Rhodamine 6G (R6G), a positively charged dye, was selected as a model drug for pH-sensitive DDS. R6G was encapsulated in the HAP/Alg nanoparticles upon synthesis, and its loading efficiency could reach up to approximately 63.0%. The in vitro release behavior of the loaded R6G at different pH values was systematically studied, and the results indicated that more R6G molecules were released at lower pH conditions. For example, after releasing for 8 h, the release amount of R6G at pH 2.0 was 2.53-fold the amount at pH 7.4. We attributed this pH-sensitive release behavior to the dissolution of the HAP core in acidic conditions. The results of the MTT assay and confocal laser scanning microscopy indicated that the HAP@Alg were successfully uptaken by liver cancer cells (HepG2) without apparent cytotoxicity. The synthesized HAP@Alg nanoparticles show great potential as drug nanovehicles with high biocompatibility, enhanced drug loading, and pH-responsive features for future intracellular DDS.
ACS Appl Mater Interfaces 2012 Dec
PMID:Cosynthesis of cargo-loaded hydroxyapatite/alginate core-shell nanoparticles (HAP@Alg) as pH-responsive nanovehicles by a pre-gel method. 2315 Dec 16

Methionine S-adenosyltransferase 2A (MAT2A) is the catalytic subunit for synthesis of S-adenosylmethionine (SAM), the principal methyl donor in many biological processes. MAT2A is up-regulated in many cancers, including liver cancer and colorectal cancer (CRC) and is a potentially important drug target. We developed a family of fluorinated N,N-dialkylaminostilbene agents, called FIDAS agents, that inhibit the proliferation of CRC cells in vitro and in vivo. Using a biotinylated FIDAS analogue, we identified the catalytic subunit of MAT2A as the direct and exclusive binding target of these FIDAS agents. MAT2B, an associated regulatory subunit of MAT2A, binds indirectly to FIDAS agents through its association with MAT2A. FIDAS agents inhibited MAT2A activity in SAM synthesis, and depletion of MAT2A by shRNAs inhibited CRC cell growth. A novel FIDAS agent delivered orally repressed CRC xenografts in athymic nude mice. These findings suggest that FIDAS analogues targeting MAT2A represent a family of novel and potentially useful agents for cancer treatment.
ACS Chem Biol 2013 Apr 19
PMID:Fluorinated N,N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A. 2336 77

The hepatitis C virus (HCV) infects an estimated 150 million people worldwide and is the major cause of viral hepatitis, cirrhosis, and liver cancer. The available antiviral therapies, which include PEGylated interferon, ribavirin, and one of the HCV NS3/4A protease inhibitors telaprevir or boceprevir, are ineffective for some patients and cause severe side effects. More potent NS3/4A protease inhibitors are in clinical development, but the long-term effectiveness of these drugs is challenged by the development of drug resistance. Here, we investigated the role of macrocycles in the susceptibility of NS3/4A protease inhibitors to drug resistance in asunaprevir, danoprevir, vaniprevir, and MK-5172, with similar core structures but varied P2 moieties and macrocyclizations. Linear and macrocyclic analogues of these drugs were designed, synthesized, and tested against wild-type and drug-resistant variants R155K, V36M/R155K, A156T, and D168A in enzymatic and antiviral assays. Macrocyclic inhibitors were generally more potent, but the location of the macrocycle was critical for retaining activity against drug-resistant variants: the P1-P3 macrocyclic inhibitors were less susceptible to drug resistance than the linear and P2-P4 macrocyclic analogues. In addition, the heterocyclic moiety at P2 largely determined the inhibitor resistance profile, susceptibility to drug resistance, and the extent of modulation by the helicase domain. Our findings suggest that to design robust inhibitors that retain potency to drug-resistant NS3/4A protease variants, inhibitors should combine P1-P3 macrocycles with flexible P2 moieties that optimally contact with the invariable catalytic triad of this enzyme.
ACS Chem Biol 2013 Jul 19
PMID:Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. 2359 83

Multifunctional theranostic nanoparticles represent an emerging agent with the potential to offer extremely sensitive diagnosis and targeted cancer therapy. Herein, we report the synthesis and characterization of a multifunctional theranostic agent (referred to as LA-LAPNHs) for targeted magnetic resonance imaging/computed X-ray tomography (MRI/CT) dual-mode imaging and photothermal therapy of hepatocellular carcinoma. The LA-LAPNHs were characterized as having a core-shell structure with the gold nanoparticles (AuNPs)@polydopamine (PDA) as the inner core, the indocyanine green (ICG), which is electrostatically absorbed onto the surface of PDA, as the photothermal therapeutic agent, and the lipids modified with gadolinium-1,4,7,10-tetraacetic acid and lactobionic acid (LA), which is self-assembled on the outer surface as the shell. The LA-LAPNHs could be selectively internalized into the hepatocellular cell line (HepG2 cells) but not into HeLa cells due to the specific recognition ability of LA to asialoglycoprotein receptor. Additionally, the dual-mode imaging ability of the LA-LAPNH aqueous solution was confirmed by enhanced MR and CT imaging showing a shorter T1 relaxation time and a higher Hounsfield unit value, respectively. In addition, the LA-LAPNHs showed significant photothermal cytotoxicity against liver cancer cells with near-infrared irradiation due to their strong absorbance in the region between 700 and 850 nm. In summary, this study demonstrates that LA-LAPNHs may be a promising candidate for targeted MR/CT dual-mode imaging and photothermal therapy of hepatocellular carcinoma.
ACS Appl Mater Interfaces 2014 Aug 27
PMID:Lipid-AuNPs@PDA nanohybrid for MRI/CT imaging and photothermal therapy of hepatocellular carcinoma. 2509 Jun 4

We report the development of a lactobionic acid (LA)-modified multifunctional dendrimer-based carrier system for targeted therapy of liver cancer cells overexpressing asialoglycoprotein receptors. In this study, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and LA (or polyethylene glycol (PEG)-linked LA, PEG-LA), followed by acetylation of the remaining dendrimer terminal amines. The synthesized G5.NHAc-FI-LA or G5.NHAc-FI-PEG-LA conjugates (NHAc denotes acetamide groups) were used to encapsulate a model anticancer drug doxorubicin (DOX). We show that both conjugates are able to encapsulate approximately 5.0 DOX molecules within each dendrimer and the formed dendrimer/DOX complexes are stable under different pH conditions and different aqueous media. The G5.NHAc-FI-PEG-LA conjugate appears to have a better cytocompatibility, enables a slightly faster DOX release rate, and displays better liver cancer cell targeting ability than the G5.NHAc-FI-LA conjugate without PEG under similar experimental conditions. Importantly, the developed G5.NHAc-FI-PEG-LA/DOX complexes are able to specifically inhibit the growth of the target cells with a better efficiency than the G5.NHAc-FI-LA/DOX complexes at a relatively high DOX concentration. Our results suggest a key role played by the PEG spacer that affords the dendrimer platform with enhanced targeting and therapeutic efficacy of cancer cells. The developed LA-modified multifunctional dendrimer conjugate with a PEG spacer may be used as a delivery system for targeted liver cancer therapy and offers new opportunities in the design of multifunctional drug carriers for targeted cancer therapy applications.
ACS Appl Mater Interfaces 2014 Sep 24
PMID:Multifunctional lactobionic acid-modified dendrimers for targeted drug delivery to liver cancer cells: investigating the role played by PEG spacer. 2518 74


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