Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The safe and efficient delivery of DNA remains the major barrier to the clinical application of non-viral gene therapy. Here, we present novel, biodegradable polymers for gene delivery that are capable of simple graft modification and demonstrate the ability to respond to intracellular conditions. We synthesized poly(beta-amino ester)s using a new amine monomer, 2-(pyridyldithio)-ethylamine (PDA). These cationic, degradable polymers contain pyridyldithio functionalities in the side chains that react with high specificity toward thiol ligands. This reactivity is demonstrated using both mercaptoethylamine (MEA) and the thiol peptide RGDC, a ligand that binds with high affinity to certain integrin receptors. These two polymer derivatives displayed strong DNA binding as determined using electrophoresis and dye exclusion assays. In addition, the MEA-based polymer and plasmid DNA were shown to self-assemble into cationic complexes with effective diameters as low as 100 nm. Furthermore, this DNA binding ability was substantially reduced in response to intracellular glutathione concentrations, which may aid in DNA unpackaging inside the cell. These complexes also displayed low cellular toxicity and were able to mediate transfection at levels comparable to PEI in human hepatocellular carcinoma cells. These results suggest that PDA-based poly(beta-amino ester)s may serve as a modular platform for polymer-mediated gene delivery.
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PMID:Synthesis of poly(beta-amino ester)s with thiol-reactive side chains for DNA delivery. 1700 66

Percutaneous radiofrequency thermal ablation (RFA) is an effective and safe therapeutic modality in the management of liver malignancies, performed with ultrasound guidance. Potential complications of RFA include liver abscess, ascites, pleural effusion, skin burn, hypoxemia, pneumothorax, subcapsular hematoma, hemoperitoneum, liver failure, tumour seeding, biliary lesions. Here we describe for the first time a case of biliary gastric fistula occurred in a 66-year old man with a Child's class A alcoholic liver cirrhosis as a complication of RFA of a large hepatocellular carcinoma lesion in the III segment. In the light of this case, RFA with injection of saline between the liver and adjacent gastrointestinal tract, as well as laparoscopic RFA, ethanol injection (PEI), or other techniques such as chemoembolization, appear to be more indicated than percutaneous RFA for large lesions close to the gastrointestinal tract.
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PMID:A case of biliary gastric fistula following percutaneous radiofrequency thermal ablation of hepatocellular carcinoma. 1727 8

This study communicates the molecular design, preparation, and biological application of novel symmetric amphiphilic polycationic dendritic poly(L-lysine)-b-poly(L-lactide)-b-dendritic poly(L-lysine) D2-LLA15-D2 bearing two two-generation poly(L-lysine) PLL dendrons D2 and a central hydrophobic biodegradable poly(L-lactide) block LLA15. First, an amino-protected precursor of L1-OH was designed and synthesized and was further employed to prepare L1-LLA15 with an organic 4-(dimethylamino)-pyridine-mediated living-ring-opening polymerization of l-lactide. Subsequently, the hydroxy end-capped L1-LLA15 was coupled to synthesize a new triblock L1-LLA15-L1 with two one-generation amino-protected PLL dendrons L1. Furthermore, with a repeated trifluoroacetic-acid-mediated amino deprotection-protection cycle, new amphiphilic triblock D2-LLA15-D2 was successfully prepared. By means of NMR, mass spectrometry, and gel permeation chromatography, these synthetic precursors and final amphiphilic product were characterized to bear well-defined triblock structures. In addition, this synthesized amphiphilic triblock polycationic macromolecule was applied as a new polycationic plasmid DNA carrier, and its DNA binding affinity was examined via an agarose electrophoresis and a fluorescence titration assay along with two important references of hydrophilic dendritic D2-HEX-D2 and double-hydrophilic D2-PEG-4K-D2 bearing the same two D2 dendrons; much enhanced DNA binding affinity was interestingly revealed for the new amphiphilic structural D2-LLA15-D2. Moreover, the assembled polyplex microparticles of plasmid DNA/polycationic carrier were further analyzed by dynamic light scattering and transmission electron microscopy, indicating their averaged nanoparticle size around 150-200 nm. As for the cytotoxicity of the new D2-LLA15-D2, MTT assays were conducted with a human hepatocellular carcinoma cell line (SMMC-7721), indicating a very low cytotoxicity as compared with commercial linear PLL-23K and PEI-2K, and a DNase I degradation of the assembled polyplex particles was also done in the HBS buffer solution to evaluate their stabilities. Finally, employing the new amphiphilic D2-LLA15-D2 as gene carrier, in vitro gene transfection experiments were conducted with the SMMC-7721 cell line, indicating a transfection efficiency increase of at least 10 times higher than that of the naked plasmid DNA under a N/P charge ratio of 10. Therefore, these interesting results may provide a new possible way to construct efficient polycationic macromolecular gene carriers with low toxicity and less expensive low-generation PLL dendrons.
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PMID:Novel symmetric amphiphilic dendritic poly(L-lysine)-b-poly(L-lactide)-b-dendritic poly(L-lysine) with high plasmid DNA binding affinity as a biodegradable gene carrier. 1745 96

Radiofrequency ablation (RFA) has become mainstream among non-surgical treatment modalities in clinical settings for the treatment of hepatocellular carcinoma. We have previously described the novel combination therapy of percutaneous ethanol injection and RFA (PEI-RFA) and reported that this combination therapy was more effective than RFA alone in terms of the induced volume of coagulated necrosis and the energy requirement for the treatment. RFA instruments are mainly divided into two types according to the electrode used, either the straight or expandable type electrode. Although PEI-RFA can be performed by either of the electrodes, there may be some important differences in PEI-RFA according to the type of electrode used. In the present study, the effect of using the straight or expandable electrode in PEI-RFA was evaluated by analyzing the ablation time, volume of coagulated necrosis, the energy requirement for ablation and the amount of injected ethanol into HCC. The comparative study showed that ablation time, total energy requirement and per unit volume of energy requirement for whole and marginal coagulated necrosis were significantly smaller in the group treated with the expandable electrode (E group) than those in the group treated with the straight electrode (S group). The volume of coagulated necrosis was similar between these groups. In group E, the amount of injected ethanol showed a positive correlation with the volume of coagulated necrosis and the size of the tumors. These results suggest that prior injection of ethanol works mainly by shortening the time and energy requirement for ablation in the time-lag PEI-RFA using the expandable electrode. Thus, prior injection of ethanol before RFA may make RFA treatment less invasive in the time-lag PEI-RFA using the expandable electrode as previously shown HCC cases treated with straight electrode.
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PMID:Comparative study of the effects of percutaneous ethanol injection and radiofrequency ablation in cases treated with a straight or expandable electrode. 1791 85

A great challenge for gene therapy is to develop a high efficient gene delivery system with low toxicity. Nonviral vectors are still attractive although the current agents displayed some disadvantages (i.e., low transfection efficiency, high toxicity). To overcome the high toxicity of poly(ethylene imine) (PEI) and low transfection efficiency of PEGylated PEI (PEG-PEI), we linked a cell specific target molecule folate (FA) on poly(ethylene glycol) (PEG) and then grafted the FA-PEG onto hyperbranched PEI 25kDa. The FA-PEG- grafted-hyperbranched-PEI (FA-PEG-PEI) effectively condensed plasmid DNA (pDNA) into nanoparticles with positive surface charge under a suitable N/P ratio. Tested in deferent cell lines (i.e., HEK 293T, glioma C6 and hepatoma HepG2 cells), no significant cytotoxicity of FA-PEG-PEI was added to PEG-PEI. More importantly, significant transfection efficiency was exhibited in FA-targeted cells. Reporter assay showed that FA-PEG-PEI/pDNA complexes had significantly higher transgene activity than that of PEI/pDNA in folate-receptor (FR) positive (HEK 293T and C6) cells but not FR-negative (HepG2) cells. These results indicated that FA-PEG-PEI might be a promising candidate for gene delivery with the characteristics of good biocompatibility, potential biodegradability, and relatively high gene transfection efficiency.
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PMID:Synthesis and characterization of folate-PEG-grafted-hyperbranched-PEI for tumor-targeted gene delivery. 1820 60

PEGylation which is reversed after the therapeutic agent reaches the target cell presents an attractive feature for drug, protein or nucleic acid delivery. Amine-reactive, endosomal pH cleavable polyethylene glycol aldehyde-carboxypyridylhydrazone, N-hydroxysuccinimide esters (PEG-HZN-NHS) were synthesized and applied for bioreversible surface shielding of DNA polyplexes. Monofunctional mPEG-HZN-NHS was synthesized by reacting succinimidyl hydraziniumnicotinate with mPEG-butyraldehyde (20 kDa). Bifunctional OPSS-PEG-HZN-NHS was synthesized analogously via a omega-2-pyridyldithio-PEG (10 kDa) propionaldehyde intermediate. Polyethylenimine (PEI) polyplexes were reacted with the pH-sensitive (mPEG-HZN-NHS) or the corresponding stable (mPEG-NHS) reagent. Both types of polyplexes remained shielded at pH 7.4 as demonstrated by particle size and zeta potential measurements after 4h of incubation at 37 degrees C. Polyplex deshielding at endosomal pH 5 was observed only with the mPEG-HZN-NHS shielded particles. This was confirmed by fluorescence correlation spectroscopy using the analogous Alexa-488 fluorescently labeled bifunctional PEGylation reagents. Luciferase gene transfections with epidermal growth factor (EGF) containing polyplexes using EGF-receptor overexpressing hepatoma HUH7 cells showed an up to 16-fold enhancement in gene expression with the reversibly shielded polyplexes as compared to stably shielded polyplexes. Consistently, the reversibly shielded polyplexes mediated also an enhanced tumor specific in vivo transgene expression after intravenous administration in a subcutaneous HUH7 tumor model in SCID mice.
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PMID:Amine-reactive pyridylhydrazone-based PEG reagents for pH-reversible PEI polyplex shielding. 1858 70

A human hepatoma cell line (HepG2) was cultured on positively and negatively charged polyelectrolytes. Cell/surface adhesion and cell shape evolution were followed with quartz microbalance with dissipation (QCM-D) and optical microscopy as a function of time, respectively. In particular, substrates coated with poly(ethyleneimine) (PEI) led to fast cell attachment and further spreading, with average maximum frequency Deltaf = 79 Hz and dissipation DeltaD = 40 x 10(-6). On the contrary, no cell spreading was observed on poly(sodium-4-styrenesulfonate) (PSS), with Deltaf = 33 Hz and DeltaD = 4.5 x 10(-6). Atomic force microscopy (AFM) was used to investigate the influence of cell shape on its mechanical properties. Considering the cells as an homogenous solid material, the corresponding elastic modulus was estimated using the Hertz model. The elastic modulus was calculated at the central part of the cell, and the average values obtained were 191 +/- 14 Pa and 941 +/- 58 Pa for cells adsorbed on PSS and PEI, respectively. Thus, different cell-substrate interaction implied different cell mechanical properties reflected in a higher elastic modulus for stronger cell/substrate interaction. The combination of QCM-D, AFM, and optical microscopy allowed the online study of the cell adhesion process, and the mechanical properties of the adhered cells.
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PMID:Substrate influence on cell shape and cell mechanics: HepG2 cells spread on positively charged surfaces. 1948 48

A simple and sensitive method has been proposed to determine a trace level of alpha-fetoprotein (AFP), hepatocellular carcinoma biomarker, using poly(methyl methacrylate) (PMMA) microfluidic chips coupled with electrochemical detection system. The PMMA microchannels have been modified with poly(ethyleneimine) (PEI) containing abundant NH(2) groups to covalently immobilize AFP monoclonal antibody. Afterward, the antigen AFP and horseradish peroxidase (HRP)-conjugated AFP antibody can sequentially bind through antigen-antibody specific interaction. Atomic force microscopy (AFM) and confocal fluorescence microscope (CFFM) were utilized to characterize the surface topography and protein immobilization after modification. Coupled with three-electrode electrochemical detection system, the immunochip can perform the detection limit of AFP down to 1 pg mL(-1), and achieve a detectable linear concentration range of 1-500 pg mL(-1) by differential pulse voltammetry (DPV). The on-chip immunoassay platform can not only provide rapid and sensitive detection for target proteins but also be resistant to non-specific adsorption of proteins, which contributes to the detection of low-level protein in real sample. Finally, AFP existing in healthy human serum was detected to demonstrate the utility of the immunochip. The result shows that the proposed approach is feasible and has the potential application in clinical analysis and diagnosis.
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PMID:Microchip-based ELISA strategy for the detection of low-level disease biomarker in serum. 1972 Jan 77

Superselective TACE is defined as TACE from the distal portion of the feeding subsegmental hepatic artery to evoke strong ischemic effects on a small area of the liver, thus avoiding damage to liver function. Lipiodol (iodized oil) is semi-fluid, and it can flow into the surrounding portal venules and hepatic sinusoids through peribiliary plexus (PBP) and the drainage route from the hypervascular HCC. Therefore, the reversed flow from the hepatic sinusoids and portal venules to the peripheral portion of the tumor and daughter nodules can be blocked by Lipiodol injected before a particulate embolus (such as gelatin sponge particles). Common complications of superselective TACE are mild local pain and fever and temporary minimal changes of liver function. Reported CR ratio of definitely hypervascular HCC are around 30-60% by superselective TACE with Lipiodol for hypervascular HCC less than 5 cm. According to a nationwide survey by the Liver Cancer Study Group of Japan (LCSGJ), overall 5-year survival rate was 26% in patients with HCCs not indicated for surgery or RFA (PEI), mainly treated by segmental or subsegmental TACE using Lipiodol. Therefore, this TACE technique should be widely introduced as the first line technique for TACE therapy of HCC.
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PMID:Interventional oncology: new options for interstitial treatments and intravascular approaches: superselective TACE using iodized oil for HCC: rationale, technique and outcome. 1988 39

In the EASL and AASLD guidelines, hepatic resection (HR) is considered the first option for patients in stage 0 (very early HCC). This statement was not based on randomized controlled trials (RCTs) versus other therapies, but on the oncological assumption that HR is the better procedure for obtaining complete tumor ablation including a safety margin. Subsequently, three RCTs compared percutaneous radiofrequency ablation (RFA) versus HR in patients with early HCC. All failed to demonstrate better survival in favor of HR, even though the larger size of the early stage needs a larger area of necrosis. A recent study focused on stage 0 demonstrated a sustained local complete response after RFA comparable with that of HR. All these trials established that RFA is less invasive and associated with lower complication rates and lower costs. These data suggest that RFA can be considered the first option for operable patients with very early HCC. Other options (HR, PEI, selective TAE/TACE) can be used as salvage therapy for the few cases in which RFA is unsuccessful or unfeasible.
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PMID:Single HCC smaller than 2 cm: surgery or ablation: interventional oncologist's perspective. 1989 Jun


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