Enhanced Photosensing and Photodynamic Treatment of Colon Cancer Cells Using Methoxy Poly(ethylene glycol)-Conjugated Chlorin e6.

Nanophotosensitizer composed of methoxy poly(ethylene glycol) (MePEG) and chlorin e6 (Ce6) (abbreviated as Pe6) was synthesized for efficient delivery of Ce6 to the colon cancer cells. Pe6 nanophotosensitizer has small diameter less than 100 nm with spherical shape and core-shell structure. They were activated in aqueous solution while Ce6 was quenched due to its poor aqueous solubility. They showed no intrinsic cytotoxicity against normal cells and colon cancer cells. Pe6 nanophotosensitizers showed enhanced cellular uptake, phototoxicity, and reactive oxygen species (ROS) generation at in vitro cell culture experiment. Furthermore, they showed improved tumor tissue penetration and accumulation in vivo animal studies. We suggested Pe6 nanophotosensitizers as an ideal candidate for PDT of colon cancer.

Dual Stimuli-Responsive Vesicular Nanospheres Fabricated by Lipopolymer Hybrids for Tumor-Targeted Photodynamic Therapy.

Smart delivery system of photosensitizer chlorin e6 (Ce6) has been developed for targeted photodynamic therapy (PDT). Simple self-assemblies of the mixtures comprising soybean lecithin derived phosphatidylcholine (PC), phosphatidylethanolamine-poly(L-histidine)40 (PE-p(His)40), and folic acid (FA) conjugated phosphatidylethanolamine-poly(N-isopropylacrylamide)40 (PE-p(NIPAM)40-FA) in different ratios yield smart nanospheres characterized by (i) stable and uniform particle size (∼100 nm), (ii) positive surface charge, (iii) high hydrophobic drug (Ce6) loading efficiency up to 45%, (iv) covalently linked targeting moiety, (v) low cytotoxicity, and (vi) smartness showing p(His) block oriented pH and p(NIPAM) oriented temperature responsiveness. The Ce6-encapsulated vesicular nanospheres (Ce6@VNS) were used to confirm the efficiency of cellular uptake, intracellular distribution, and phototoxicity against KB tumor cells compared to free Ce6 at different temperature and pH conditions. The Ce6@VNS system showed significant photodynamic therapeutic efficiency on KB cells than free Ce6. A receptor-mediated inhibition study proved the site-specific delivery of Ce6 in targeted tumor cells.

Nano-Self Assembled Photosensitizer Composed of Methoxy Poly(ethylene glycol)-Conjugated Chlorin e6 for Enhanced Photosensing of HCT116 Cells.

We synthesized methoxy poly(ethylene glycol) (MPEG)-chlórin e6 (Ce6) conjugates to increase aqueous solubility of Ce6, to fabricate nanoparticles, and to improve tumor targetability of Ce6. MPEG-Ce6 conjugates (abbreviated as Pe6) associated in the aqueous solution as a nanoparticle. Pe6 nanoparticles have small diameter less than 100 nm, spherical shape, and core-shell structure in the aqueous environment. They have improved photophysical properties compared to Ce6 itself. Photosensitivity of Pe6 nanoparticles were studied using HCT116 human colon carcinoma cells. Pe6 nanoparticles practically have no dark-toxicity against HCT116 human colon carcinoma cells while they showed enhanced cellular uptake, phototoxicity, and ROS generation at in vitro cell culture experiment. Furthermore, they showed improved tumor tissue penetration and accumulation in vivo animal studies. We suggested Pe6 nanoparticles as an ideal candidate for PDT of colon cancer.

Cisplatin-incorporated nanoparticles of methoxy poly(ethylene glycol)-b-poly(L-glutamic acid) copolymer.

We fabricated cisplatin-incorporated nanoparticles using block copolymer composed of methoxy poly(ethylene glycol) (MPEG) and poly(L-glutamic acid) (PGA) (abbreviated as GE). For synthesis of block copolymer, MPEG was directly conjugated to the terminal amine of PGA. Cisplatin-incorporated nanoparticles was prepared by ion complex formation of cisplatin and PGA domain of block copolymer. Size of cisplatin-incorporated nanoparticles was less than 200 nm at particle size measurement and their shapes were spherical at TEM observation. To study drug release properties, cispaltin release from nanoparticles were performed at phosphate-buffered saline (PBS, 0.01 M, pH 7.4) and distilled water, indicating that cisplatin release rate at PBS was approximately three times higher than that of deionized water. The cell growth inhibition of cisplatin incorporated nanoparticles in vitro was tested with HuCC-T1 cells. Cisplatin-incorporated nanoparticles were effectively inhibited tumor cell growth as similar as cisplatin itself. In other words, nanoparticles showed decreased inherent cytotoxicity compared to cisplatin against normal cells. We suggest that cisplatin incorporated GE nanoparticles is a good candidate for antitumor drug targeting.

Effect of 5-aminolevulinic acid-encapsulate liposomes on photodynamic therapy in human cholangiocarcinoma cells.

Intracellular protoporphyrin IX (PpIX) generation following administration of 5-aminolevulinic acid (ALA) has been used in photodynamic therapy (PDT). Subsequent irradiation can lead to selective damage to photosensitizer-treated cells or tissues. In the present work, we describe the enhancement of ALA-induced PpIX accumulation using a liposome carrier. ALA-containing liposomes (Lipo-ALA) were prepared using dipalmitoyl-phosphatidyl choline and in vitro PDT effect was investigated against human cholangiocarcinoma HuCC-T1 cells. Lipo-ALA increased the uptake efficiency into tumor cells compared to ALA itself, which increased the phototoxic effect. A positive relationship was evident between small particle size, PpIX accumulation and cell death after Lipo-ALA based PDT.

Self-assembled polymeric micelles based on hyaluronic acid-g-poly(D,L-lactide-co-glycolide) copolymer for tumor targeting.

Graft copolymer composed hyaluronic acid (HA) and poly(D,L-lactide-co-glycolide) (PLGA) (HAgLG) was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA) to have amine end group in the end of chain (PLGA-amine). PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50-200 nm. Doxorubicin (DOX)-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC)-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting.

One-pot synthesis of linear-hyperbranched amphiphilic block copolymers based on polyglycerol derivatives and their micelles.

This paper describes the one-pot synthesis of a polyglycidol (PG)-based polymer, poly(ethoxyethyl glycidyl ether) (PEEGE)-b-[hyperbranched polyglycerol (hbPG)-co-PEEGE]x/y, its micelle formulation, and the ability to encapsulate a model therapeutic molecule. Amphiphilic block copolymers were prepared by the sequential addition of ethoxyethyl glycidyl ether (EEGE) to glycidol. The composition of the block copolymers varied from 62:38 to 92:8. Block copolymers with composition x:y≥66:34 were soluble only in organic solvents. Micelles were formulated by injection of deionized water into a tetrahydrofuran block copolymer solution with or without pyrene as a model hydrophobic molecule. The critical micelle concentration was 18.2-30.9 mg/L, and the micelle size was 100-250 nm. The pyrene-containing micelle rapidly collapsed on acidic exposure, allowing conversion of hydrophobic PEEGE to hydrophilic PG, thus, facilitating the release of the encapsulated pyrene. Cytotoxicity data showed high biocompatibility of PG-based block copolymers, suggesting their potential as a drug delivery carrier.

Dual stimuli-responsive poly(N-isopropylacrylamide)-b-poly(L-histidine) chimeric materials for the controlled delivery of doxorubicin into liver carcinoma.

A series of dual stimuli responsive synthetic polymer bioconjugate chimeric materials, poly(N-isopropylacrylamide)55-block-poly(L-histidine)n [p(NIPAM)55-b-p(His)n] (n=50, 75, 100, 125), have been synthesized by employing reversible addition-fragmentation chain transfer polymerization of NIPAM, followed by ring-opening polymerization of α-amino acid N-carboxyanhydrides. The dual stimuli responsive properties of the resulting biocompatiable and membrenolytic p(NIPAM)55-b-p(His)n polymers are investigated for their use as a stimuli responsive drug carrier for tumor targeting. Highly uniform self-assembled micelles (∼55 nm) fabricated by p(NIPAM)55-b-p(His)n polymers display sharp thermal and pH responses in aqueous media. An anticancer drug, doxorubicin (Dox), is effectively encapsulated in the micelles and the controlled Dox release is investigated in different temperature and pH conditions. Antitumor effect of the released Dox is also assessed using the HepG2 human hepatocellular carcinoma cell lines. Dox molecules released from the [p(NIPAM)55-b-p(His)n] micelles remain biologically active and have stimuli responsive capability to kill cancer cells. The self-assembling ability of these hybrid materials into uniform micelles and their efficiency to encapsulate Dox makes them a promising drug carrier to cancer cells. The new chimeric materials thus display tunable properties that can make them useful for a molecular switching device and controlled drug delivery applications needing responses to temperature and pH for the improvement of cancer chemotherapy.

Metallic or plastic stent for bile duct obstruction in ampullary cancer?

BACKGROUND AND AIMS: Although ampullary cancer is a relatively uncommon malignancy, it is frequently associated with biliary obstruction. Endoscopic biliary drainage is regarded as a palliative treatment of choice for patients with inoperable ampullary cancer. However, there are no data concerning choice of stent in this patient population. The objective of this study was to compare the efficacy of metallic and plastic stents for biliary obstruction in patients with ampullary cancer. METHODS: Thirty-seven patients (15 men and 22 women; median age 74.7 years) with ampullary cancer treated with endoscopic biliary drainage were enrolled. Metallic and two plastic stents were placed in 17 and 20 patients, respectively. Clinical success, stent patency, and stent malfunction were evaluated. RESULTS: Clinical success was achieved in all patients (100%). The median period of stent patency was 132.7 days in the metallic stent group and 128.5 days in the plastic stent group (P > 0.05). Stent malfunctions developed in 17 and 19 patients in the metallic and plastic stent groups, respectively. Stent occlusion occurred in 15 (88.2%) and 15 (75%) patients and stent migration occurred in two (11.8%) and four (20%) patients in the metallic and plastic stent groups, respectively. CONCLUSIONS: Endoscopic biliary drainage using metallic or plastic stents is effective for initial endoscopic palliation in patients with obstructive jaundice because of ampullary cancer. Although metallic and plastic stents had similar clinical effect, it seems reasonable to choose two plastic stents as the first option in patients with ampullary cancer considering the cost-effectiveness.

[Clinical efficacy and safety of the combination therapy of peginterferon alpha and ribavirin in cirrhotic patients with HCV infection].

BACKGROUND/AIMS: The combination therapy of peginterferon (PEG-IFN) and ribavirin is the standard treatment for hepatitis C virus (HCV) infection. However, few trials have involved patients with cirrhosis. The purpose of this study was to elucidate the efficacy and safety of treatment with PEG-IFN and ribavirin in patients with cirrhosis associated with HCV infection. METHOD: A total of 65 patients were treated with PEG-IFN alpha-2a/ribavirin (n=32) or PEG-IFN alpha-2b/ribavirin (n=33). PEG-IFN alpha-2a and PEG-IFN alpha-2b were administered at doses of 180 microg/week and 1.5 microg/kg/week, respectively, and ribavirin was administered orally at doses of 800-200 mg. Patients with HCV genotype 1 and genotype non-1 were treated for 48 and 24 weeks, respectively. The treatment response was assessed based on the sustained virologic response (SVR). RESULTS: The early virologic response (EVR), end-of-treatment response (ETR), and SVR were 70.0%, 52.0%, and 24.0%, respectively, in genotype 1 (n=50). In genotype non-1 (n=15), the ETR was 53.3% and the SVR was 33.3%. The overall SVR did not differ with genotype (1 vs non-1, 24.0% vs. 33.3%; P=0.471) or between decompensated cirrhosis and compensated cirrhosis (20.0% vs. 27.3%, P=0.630). Ten patients developed cirrhotic complications during the treatment, and 11 stopped treatment due to treatment-related adverse events. CONCLUSION: The combination therapy of PEG-IFN and ribavirin exhibited a low efficacy in cirrhotic patients with HCV infection and was associated with frequent serious complications. However, with careful management of complications, the therapy may have a considerable efficacy in some patients with cirrhosis and HCV infection.

Redox- and pH-Responsive Nanoparticles Release Piperlongumine in a Stimuli-Sensitive Manner to Inhibit Pulmonary Metastasis of Colorectal Carcinoma Cells.

Redox-responsive nanoparticles having a diselenide linkage were synthesized to target pulmonary metastasis of cancer cells. Methoxy poly(ethylene glycol)-grafted chitosan (ChitoPEG) was crosslinked using selenocystine-acetyl histidine (Ac-histidine) conjugates (ChitoPEGse) for stimuli-responsive delivery of piperlongumine (PL). ChitoPEGse nanoparticles swelled in an acidic environment and became partially disintegrated in the presence of H2O2, resulting in an increase of particle size and in a size distribution having multimodal pattern. PL release increased under acidic conditions and in the presence of H2O2. Uptake of ChitoPEGse nanoparticles by CT26 cells significantly increased in acidic and redox state. PL-incorporated ChitoPEGse nanoparticles (PL NPs) showed similar anticancer activity in vitro against A549 and CT26 cells compared to PL itself. PL NP showed superior anticancer and antimetastatic activity in an in vivo CT26 cell pulmonary metastasis mouse model. Furthermore, an immunofluorescence imaging study demonstrated that PL NP conjugates were specifically delivered to the tumor mass in the lung. Conclusively, ChitoPEGse nanoparticles were able to be delivered to cancer cells with an acidic- or redox state-sensitive manner and then efficiently targeted pulmonary metastasis of cancer cells since ChitoPEGse nanoparticles have dual pH- and redox-responsiveness.

Local delivery of a cancer-favoring oncolytic vaccinia virus via poly (lactic-co-glycolic acid) nanofiber for theranostic purposes.

Local delivery of viruses via nanomaterials has been demonstrated in the treatment of colon cancer. A cancer-favoring oncolytic vaccinia virus (CVV), which is an evolutionary cancer-favoring engineered vaccinia virus carrying the green fluorescent protein (GFP) gene, has antitumor efficacy in drug-resistant colon cancer and metastatic liver cells. Here, we present the antitumor efficacy of a CVV coated a poly lactic-co-glycolic acid (PLGA) nanofiber for local drug delivery in theranostic approaches. In vitro- and in vivo-based analyses using mouse colon carcinoma models confirmed the therapeutic efficacy of CVV-PLGA nanofibers through diagnostic localization of the tumors and reduced tumor burden as a result of enhanced apoptosis. We propose that the CVV-PLGA nanofiber may be used for theranostic purposes in cancer therapy.

Vorinostat-eluting poly(DL-lactide-co-glycolide) nanofiber-coated stent for inhibition of cholangiocarcinoma cells.

PURPOSE: The aim of this study was to fabricate a vorinostat (Zolinza™)-eluting nanofiber membrane-coated gastrointestinal (GI) stent and to study its antitumor activity against cholangiocarcinoma (CCA) cells in vitro and in vivo. METHODS: Vorinostat and poly(DL-lactide-co-glycolide) dissolved in an organic solvent was sprayed onto a GI stent to make a nanofiber-coated stent using an electro-spinning machine. Intact vorinostat and vorinostat released from nanofibers was used to assess anticancer activity in vitro against various CCA cells. The antitumor activity of the vorinostat-eluting nanofiber membrane-coated stent was evaluated using HuCC-T1 bearing mice. RESULTS: A vorinostat-incorporated polymer nanofiber membrane was formed on the surface of the GI stent. Vorinostat was continuously released from the nanofiber membrane over 10 days, and its release rate was higher in cell culture media than in phosphate-buffered saline. Released vorinostat showed similar anticancer activity against various CCA cells in vitro compared to that of vorinostat. Like vorinostat, vorinostat released from nanofibers induced acetylation of histone H4 and inhibited histone deacetylases 1⋅3⋅4/5/7 expression in vitro and in vivo. Furthermore, vorinostat nanofibers showed a higher tumor growth inhibition rate in HuCC-T1 bearing mice than vorinostat injections. CONCLUSION: Vorinostat-eluting nanofiber membranes showed significant antitumor activity against CCA cells in vitro and in vivo. We suggest the vorinostat nanofiber-coated stent may be a promising candidate for CCA treatment.

Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery.

BACKGROUND: Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol) (MPEG)-doxorubicin (DOX) conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting. METHODS: Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP). Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP). Nanoparticles were then prepared using a dialysis procedure. RESULTS: The synthesized DendGDP was confirmed with (1)H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and revealed stronger fluorescence intensity than at other body sites while doxorubicin and DendDP nanoparticles showed strong fluorescence intensity in the various organs, indicating that DendGDP has cathepsin B sensitivity. CONCLUSION: DendGDP is sensitive to cathepsin B in tumor cells and can be used as a cathepsin B-responsive drug targeting strategy. We suggest that DendGDP is a promising vehicle for cancer cell targeting.

Crosslinked poly(ethylene glycol) hydrogels with degradable phosphamide linkers used as a drug carrier in cancer therapy.

A series of degradable, water-swellable PEGs are prepared using crosslinking between primary amines of N,N',N″-tris(2-aminoethyl)phosphoric triamide (TAEPT) and diglycidyl ether of epichlorohydrin-modified PEGs (EMPs). In the crosslinking process, the glycidyl ether is mainly consumed by the -NH2 of TAEPT and the hydroxyl generated from the opened glycidyl ethers (C-OH), producing degradable phosphonyl-amide frameworks as crosslinked points, and ether bonds as short branches, respectively. Studies on anticancer drug entrapment, chemoimmunotherapy agent delivery, degradation, and biological cytotoxicity in vitro suggest that the generated hydrogels have great potential as biomaterials in biomedical applications.

Importance of the time interval between bowel preparation and colonoscopy in determining the quality of bowel preparation for full-dose polyethylene glycol preparation.

BACKGROUND/AIMS: The quality of bowel preparation (QBP) is the important factor in performing a successful colonoscopy. Several factors influencing QBP have been reported; however, some factors, such as the optimal preparation-to-colonoscopy time interval, remain controversial. This study aimed to determine the factors influencing QBP and the optimal time interval for full-dose polyethylene glycol (PEG) preparation. METHODS: A total of 165 patients who underwent colonoscopy from June 2012 to August 2012 were prospectively evaluated. The QBP was assessed using the Ottawa Bowel Preparation Scale (Ottawa) score according to several factors influencing the QBP were analyzed. RESULTS: Colonoscopies with a time interval of 5 to 6 hours had the best Ottawa score in all parts of the colon. Patients with time intervals of 6 hours or less had the better QBP than those with time intervals of more than 6 hours (p=0.046). In the multivariate analysis, the time interval (odds ratio, 1.897; 95% confidence interval, 1.006 to 3.577; p=0.048) was the only significant contributor to a satisfactory bowel preparation. CONCLUSIONS: The optimal time was 5 to 6 hours for the full-dose PEG method, and the time interval was the only significant contributor to a satisfactory bowel preparation.

5-aminolevulinic acid-incorporated nanoparticles of methoxy poly(ethylene glycol)-chitosan copolymer for photodynamic therapy.

PURPOSE: The aim of this study was to make 5-aminolevulinic acid (5-ALA)-incorporated nanoparticles using methoxy polyethylene glycol/chitosan (PEG-Chito) copolymer for application in photodynamic therapy for colon cancer cells. METHODS: 5-ALA-incorporated (PEG-Chito-5-ALA) nanoparticles were prepared by ion complex formation between 5-ALA and chitosan. Protoporphyrin IX accumulation in the tumor cells and phototoxicity induced by PEG-Chito-5-ALA nanoparticles were assessed using CT26 cells in vitro. RESULTS: PEG-Chito-5-ALA nanoparticles have spherical shapes with sizes diameters 200 nm. More specifically, microscopic observation revealed a core-shell structure of PEG-Chito-5-ALA nanoparticles. 1H NMR spectra showed that 5-ALA was incorporated in the core of the nanoparticles. In the absence of light irradiation, all components such as 5-ALA, empty nanoparticles, and PEG-Chito-5-ALA nanoparticles did not affect the viability of cells. However, 5-ALA or PEG-Chito-5-ALA nanoparticles induced tumor cell death under light irradiation, and the viability of tumor cells was dose-dependently decreased according to the increase in irradiation time. In particular, PEG-Chito-5-ALA nanoparticles induced increased phototoxicity and higher protoporphyrin IX accumulation into the tumor cells than did 5-ALA alone. Furthermore, PEG-Chito-5-ALA nanoparticles accelerated apoptosis/necrosis of tumor cells, compared to 5-ALA alone. CONCLUSION: PEG-Chito-5-ALA nanoparticles showed superior delivery capacity of 5-ALA and phototoxicity against tumor cells. These results show that PEG-Chito-5-ALA nanoparticles are promising candidates for photodynamic therapy of colon cancer cells.

Preclinical evaluation of sorafenib-eluting stent for suppression of human cholangiocarcinoma cells.

BACKGROUND: Cholangiocarcinoma is a malignant tumor arising from the epithelium of the bile ducts. In this study, we prepared sorafenib-loaded biliary stents for potential application as drug-delivery systems for localized treatment of extrahepatic cholangiocarcinoma. METHODS: A sorafenib-coated metal stent was prepared using an electrospray system with the aid of poly(ε-caprolactone) (PCL), and then its anticancer activity was investigated using human cholangiocellular carcinoma (HuCC)-T1 cells in vitro and a mouse tumor xenograft model in vivo. Anticancer activity of sorafenib against HuCC-T1 cells was evaluated by the proliferation test, matrix metalloproteinase (MMP) activity, cancer cell invasion, and angiogenesis assay in vitro and in vivo. RESULTS: The drug-release study showed that the increased drug content on the PCL film induced a faster drug-release rate. The growth of cancer cells on the sorafenib-loaded PCL film surfaces decreased in a dose-dependent manner. MMP-2 expression of HuCC-T1 cells gradually decreased according to sorafenib concentration. Furthermore, cancer cell invasion and tube formation of human umbilical vein endothelial cells significantly decreased at sorafenib concentrations higher than 10 mM. In the mouse tumor xenograft model with HuCC-T1 cells, sorafenib-eluting PCL films significantly inhibited the growth of tumor mass and induced apoptosis of tumor cells. Various molecular signals, such as B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter, Bcl-x, caspase-3, cleaved caspase-3, Fas, signal transducer and activator of transcription 5, extracellular signal-regulated kinases, MMP-9 and pan-janus kinase/stress-activated protein kinase 1, indicated that apoptosis, inhibition of growth and invasion was cleared on sorafenib-eluting PCL films. CONCLUSION: These sorafenib-loaded PCL films are effective in inhibiting angiogenesis, proliferation and invasion of cancer cells. We suggest that sorafenib-loaded PCL film is a promising candidate for the local treatment of cholangiocarcinoma.

Bilateral biliary drainage for malignant hilar obstruction using the 'stent-in-stent' method with a Y-stent: efficacy and complications.

BACKGROUND: The usefulness of bilateral stent placement for malignant hilar obstruction is still under debate. Nevertheless, many endoscopists advocate the placement of an endoscopic bilateral metal stent using various new devices and techniques. OBJECTIVES: We compared the technical and clinical efficacy, and the short-term and long-term complications of the 'stent-in-stent' method using a Y-stent for malignant hilar obstruction between the early and the late period of this study. MATERIALS AND METHODS: Ninety-seven patients treated with Y-stent implantation for malignant hilar obstruction were enrolled retrospectively. In 31 patients treated during the early period, bilateral Y-configured metal stents were placed for malignant hilar obstruction using the older designed Y-stent and a closed-cell second stent. The newly designed Y-stent and a slimmer open-cell second stent were introduced in 66 patients treated during the late period. New techniques learned through experience were gradually applied throughout the entire study period. RESULTS: The rate of successful placement of bilateral stents was significantly higher in patients treated during the late period than those treated during the early period (58.1 vs. 87%; P=0.001). The functional success rate was 97.3%, with no difference between the early and the late periods. Cholangitis occurred as an early complication more frequently during the early period than during the late period (16.1 vs. 1.5%; P=0.012). Cholecystitis as a late complication occurred in 21 of 76 patients (27.6%). The incidence of late complications was similar between the early and the late periods. CONCLUSION: With the development of new devices and increased technical experience, there were better outcomes during the late period compared with the early period. Endoscopic bilateral metal stenting using a Y-stent is an attractive option for the palliative treatment of malignant hilar obstruction.