• cancer cells
• chemosensitization
• ellagic acid
• epigallocatechin gallate
• nanomedicine
• tannic acid
• tannins

• Humans
• Tannins/pharmacology
• Tannins/therapeutic use
• Tannins/chemistry
• Neoplasms/drug therapy
• Neoplasms/prevention & control
• Neoplasms/pathology
• Animals
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Agents, Phytogenic/therapeutic use

• Leukemia
• Nano-delivery
• Poly(D, L-lactide-co-glycolide)
• Romidepsin

• Humans
• Depsipeptides/administration & dosage
• Depsipeptides/chemistry
• Depsipeptides/pharmacology
• Histone Deacetylase Inhibitors/administration & dosage
• Histone Deacetylase Inhibitors/chemistry
• Histone Deacetylase Inhibitors/pharmacology
• Drug Carriers/chemistry
• Drug Carriers/administration & dosage
• Nanoparticles/chemistry
• Nanoparticles/administration & dosage
• Apoptosis/drug effects
• Cell Survival/drug effects
• Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
• Drug Liberation
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Jurkat Cells
• U937 Cells
• Leukemia/drug therapy
• Cell Line, Tumor

• CRISPR/Cas tool
• biomacromolecules
• epigenetic modulators
• epigenetics
• nanocarriers
• prodrugs

• Department of Biotechnology, Ministry of Science and Technology, India

• Drug delivery
• Niosome
• SAHA
• Suberoylanilide hydroxamic acid, deacetylase inhibitor
• Vesicle
• Zolinza

• Humans
• Vorinostat/pharmacology
• Vorinostat/administration & dosage
• Vorinostat/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/chemistry
• HeLa Cells
• MCF-7 Cells
• Apoptosis/drug effects
• Liposomes
• Hydroxamic Acids/chemistry
• Hydroxamic Acids/administration & dosage
• Hydroxamic Acids/pharmacology
• Drug Carriers/chemistry
• Particle Size
• Nanoparticles/chemistry
• Drug Liberation
• Cell Survival/drug effects

• Apoptosis
• Cancer
• Cell death
• Clinical efficacy
• Epigenetic pathways
• Human and disease
• Medicine
• Oncology

• Cholangiocarcinoma (CCA)
• Diagnosis
• Nanoplatform
• Route of administration

The aim of this study is to prepare pH- and redox-sensitive nanoparticles for doxorubicin (DOX) delivery against DOX-resistant HuCC-T1 human cholangiocarcinoma (CCA) cells. For this purpose, L-histidine methyl ester (HIS) was attached to chitosan oligosaccharide (COS) via dithiodipropionic acid (abbreviated as ChitoHISss). DOX-incorporated nanoparticles of ChitoHISss conjugates were fabricated by a dialysis procedure. DOX-resistant HuCC-T1 cells were prepared by repetitive exposure of HuCC-T1 cells to DOX. ChitoHISss nanoparticles showed spherical morphology with a small diameter of less than 200 nm. The acid pH and glutathione (GSH) addition induced changes in the size distribution pattern of ChitoHISss nanoparticles from a narrow/monomodal distribution pattern to a wide/multimodal pattern and increased the fluorescence intensity of the nanoparticle solution. These results indicate that a physicochemical transition of nanoparticles can occur in an acidic pH or redox state. The more acidic the pH or the higher the GSH concentration the higher the drug release rate was, indicating that an acidic environment or higher redox states accelerated drug release from ChitoHISss nanoparticles. Whereas free DOX showed decreased anticancer activity at DOX-resistant HuCC-T1 cells, DOX-incorporated ChitoHISss nanoparticles showed dose-dependent anticancer activity. Intracellular delivery of DOX-incorporated ChitoHISss nanoparticles was relatively increased at an acidic pH and in the presence of GSH, indicating that DOX-incorporated ChitoHISss nanoparticles have superior acidic pH- and redox-sensitive behavior. In an in vivo tumor xenograft model, DOX-incorporated ChitoHISss nanoparticles were specifically delivered to tumor tissues and then efficiently inhibited tumor growth. We suggest that ChitoHISss nanoparticles are a promising candidate for treatment of CCA.

• acidic pH sensitive
• cholangiocarcinoma
• drug targeting
• nanoparticles
• redox sensitive

The natural polymer, lignin, possesses unique biodegradable and biocompatible properties, making it highly attractive for the generation of nanoparticles for targeted cancer therapy. In this study, we investigated spruce and eucalyptus lignin nanoparticles (designated as S-and E-LNPs, respectively). Both LNP types were generated from high-molecular-weight (M_w) kraft lignin obtained as insoluble residues after a five-step solvent fractionation approach, which included ethyl acetate, ethanol, methanol, and acetone. The resulting S-and E-LNPs ranged in size from 16 to 60 nm with uniform spherical shape regardless of the type of lignin. The preparation of LNPs from an acetone-insoluble lignin fraction is attractive because of the use of high-M_w lignin that is otherwise not suitable for most polymeric applications, its potential scalability, and the consistent size of the LNPs, which was independent of increased lignin concentrations. Due to the potential of LNPs to serve as delivery platforms in liver cancer treatment, we tested, for the first time, the efficacy of newly generated E-LNPs and S-LNPs in two types of primary liver cancer, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), in vitro. Both S-LNPs and E-LNPs inhibited the proliferation of HCC cells in a dose-dependent manner and did not affect CCA cell line growth. The inhibitory effect toward HCC was more pronounced in the E-LNP-treated group and was comparable to the standard therapy, sorafenib. Also, E-LNPs induced late apoptosis and necroptosis while inhibiting the HCC cell line. This study demonstrated that an elevated number of carbohydrates on the surface of the LNPs, as shown by NMR, seem to play an important role in mediating the interaction between LNPs and eukaryotic cells. The latter effect was most pronounced in E-LNPs. The novel S- and E-LNPs generated in this work are promising materials for biomedicine with advantageous properties such as small particle size and tailored surface functionality, making them an attractive and potentially biodegradable delivery tool for combination therapy in liver cancer, which still has to be verified in vivo using HCC and CCA models.

• apoptosis
• cancer treatment
• cholangiocarcinoma (CCA)
• eucalyptus lignin
• hepatocellular carcinoma (HCC)
• lignin nanoparticles (LNPs)
• primary liver cancer (PLC)
• spruce lignin

Stimuli-responsive nanoparticles are regarded as an ideal candidate for anticancer drug targeting. We synthesized glutathione (GSH) and magnetic-sensitive nanocomposites for a dual-targeting strategy. To achieve this goal, methoxy poly (ethylene glycol) (MePEG) was grafted to water-soluble chitosan (abbreviated as ChitoPEG). Then doxorubicin (DOX) was conjugated to the backbone of chitosan via disulfide linkage. Iron oxide (IO) magnetic nanoparticles were also conjugated to the backbone of chitosan to provide magnetic sensitivity. In morphological observation, images from a transmission electron microscope (TEM) showed that IO nanoparticles were embedded in the ChitoPEG/DOX/IO nanocomposites. In a drug release study, GSH addition accelerated DOX release rate from nanocomposites, indicating that nanocomposites have redox-responsiveness. Furthermore, external magnetic stimulus concentrated nanocomposites in the magnetic field and then provided efficient internalization of nanocomposites into cancer cells in cell culture experiments. In an animal study with CT26 cell-bearing mice, nanocomposites showed superior magnetic sensitivity and then preferentially targeted tumor tissues in the field of external magnetic stimulus. Nanocomposites composed of ChitoPEG/DOX/IO nanoparticle conjugates have excellent anticancer drug targeting properties.

• chitosan
• iron-oxide nanoparticle
• magnetic nanoparticle
• redox-responsiveness
• stimuli-responsiveness

• Animals
• Antibiotics, Antineoplastic/chemistry
• Antibiotics, Antineoplastic/pharmacology
• Apoptosis
• Cell Proliferation
• Chitosan/analogs & derivatives
• Chitosan/chemistry
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Doxorubicin/chemistry
• Doxorubicin/pharmacology
• Drug Liberation
• Glutathione/chemistry
• Humans
• Magnetite Nanoparticles/administration & dosage
• Magnetite Nanoparticles/chemistry
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Polyethylene Glycols/chemistry
• Polymers/chemistry
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

One of the major limitations to cancer therapies are the side effects caused by the drug interacting with any tissue in the body. There is often a balance between patient health and effectively treating the disease. To by-pass this balancing act nanoparticles are being used to deliver therapeutics straight to the tumors, acting as “Trojan Horses”. Endometrial cancers are known to have more of the cell surface protein CD44 than healthy tissues. Here, to efficiently target endometrial cancer, hyaluronic acid, which naturally binds to the CD44 protein was attached to the surface of nanoparticles and tested on microtissues or spheroids to better model a tumor and understand drug delivery performance. We show that our hyaluronic acid-nanoparticle formulations improve drug effects and interact with the cancer cells more than without this targeting agent.

Histone Deacetylase (HDAC) enzymes are upregulated in cancer leading to the development of HDAC inhibiting compounds, several of which are currently in clinical trials. Side effects associated with toxicity and non-specific targeting indicate the need for efficient drug delivery approaches and tumor specific targeting to enhance HDAC efficacy in solid tumor cancers. SAHA encapsulation within F127 micelles functionalized with a surface hyaluronic acid moiety, was developed to target endometrial cancer cells expressing elevated levels of CD44. In vitro viability and morphology analyses was conducted in both 2D and 3D models to assess the translational potential of this approach. Encapsulation enhanced SAHA delivery and activity, demonstrating increased cytotoxic efficacy in 2D and 3D endometrial cancer models. High-content imaging showed improved nanoparticle internalization in 2D and CD44 enhanced penetration in 3D models. In addition, the nano-delivery system enhanced spheroid penetration resulting in cell growth suppression, p21 associated cell cycle arrest, as well as overcoming the formation of an EMT associated phenotype observed in free drug treated type II endometrial cancer cells. This study demonstrates that targeted nanoparticle delivery of SAHA could provide the basis for improving its efficacy in endometrial cancer. Using 3D models for endometrial cancer allows the elucidation of nanoparticle performance and CD44 targeting, likely through penetration and retention within the tumor model.

• 3D models
• F127 micelles
• SAHA
• epigenetics
• gynecological oncology
• hyaluronic acid
• nanomedicines
• polymeric nanoparticles
• targeted therapeutics

Since urinary tract infections (UTIs) are closely associated with oxidative stress, we developed ROS-sensitive nanoparticles for ciprofloxacin (CIP) delivery for inhibition of UTI. Poly(D,L-lactide-co-glycolide) (PLGA)- selenocystamine (PLGA-selenocystamine) conjugates were attached to methoxypoly(ethylene glycol) (PEG) tetraacid (TA) (TA-PEG) conjugates to produce a copolymer (abbreviated as LGseseTAPEG). Selenocystamine linkages were introduced between PLGA and TA to endow reactive oxygen species (ROS) sensitivity to nanoparticles. CIP-incorporated nanoparticles of LGseseTAPEG copolymer were fabricated by W/O/W/W emulsion method. CIP-incorporated nanoparticles responded to H₂O₂ and then their morphologies were disintegrated by incubation with H₂O₂. Furthermore, particle size distribution of nanoparticles was changed from mono-modal distribution pattern to multi-modal distribution pattern by addition of H₂O₂. CIP release from nanoparticles of LGseseTAPEG copolymer was faster in the presence of H₂O₂ than in the absence of it. In antibacterial study using Escherichia coli (E. coli), free CIP and free CIP plus empty nanoparticles showed dose-dependent inhibitory effect against growth of bacteria while CIP-incorporated nanoparticles have less antibacterial activity compared to free CIP. These results were due to that CIP-incorporated nanoparticles have sustained release properties. When free CIP or CIP-incorporated nanoparticles were introduced into dialysis membrane to mimic in vivo situation, CIP-incorporated nanoparticles showed superior antibacterial activity compared to free CIP. At cell viability assay, nanoparticles of LGseseTAPEG copolymer have no acute cytotoxicity against L929 mouse fibroblast cells and CCD986sk human skin fibroblast cells. We suggest LGseseTAPEG nanoparticles are a promising candidate for CIP delivery.

• infectious disease
• reactive oxygen species
• redox-responsive
• stimuli-sensitive nanoparticles
• urethritis

• HDACi
• SAHA
• U87 glioblastoma cells
• cancer
• histone deacetylase inhibitor
• nanocarriers

• Cancer therapeutics
• Cold atmospheric plasma
• Programmed cell death
• Redox imbalance

• breast cancer
• drug resistance
• epi-drugs
• epigenetics
• nanomedicine
• targeted delivery

• APVV-16-0010 Agentúra na Podporu Výskumu a Vývoja
• APVV-16-0178 Agentúra na Podporu Výskumu a Vývoja
• 2/0271/17 Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
• 2/0138/20 Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
• 2/0052/18 Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
• INNOCENT ERA-NET EuroNanoMed II
• project VISION Horizon 2020 research and innovation program under grant agreement No. 857381
• H2020-NMBP-TO-IND-2019 SABYDOMA, contract No. 862296 ERA-NET EuroNanoMed III CELLUX

Cholangiocarcinoma (CCA) has been identified as a highly malignant cancer that can be transformed from epithelial cells of the bile duct, including intrahepatic, perihilar and extrahepatic. High-resolution imaging tools (abdominal ultrasound, computed tomography and percutaneous transhepatic cholangial drainage) are recruited for diagnosis. However, the lack of early diagnostic biomarkers and treatment evaluation can lead to serious outcomes and poor prognosis (i.e., CA19-9, MUC5AC). In recent years, scientists have established a large number of omics profiles to reveal underlying mechanisms and networks (i.e., IL-6/STAT3, NOTCH). With these results, we achieved several genomic alteration events (i.e., TP53_mut, KRAS_mut) and epigenetic modifications (i.e., DNA methylation, histone modification) in CCA cells and clinical patients. Moreover, we reviewed candidate gene (such as NF-kB, YAP1) that drive gene transcription factors and canonical pathways through transcriptomics profiles (including microarrays and next-generation sequencing). In addition, the proteomics database also indicates which molecules and their directly binding status could trigger dysfunction signatures in tumorigenesis (carbohydrate antigen 19-9, mucins). Most importantly, we collected metabolomics datasets and pivotal metabolites. These results reflect the pharmacotherapeutic options and evaluate pharmacokinetic/pharmacodynamics in vitro and in vivo. We reversed the panels and selected many potentially small compounds from the connectivity map and L1000CDS² system. In this paper, we summarize the prognostic value of each candidate gene and correlate this information with clinical events in CCA. This review can serve as a reference for further research to clearly investigate the complex characteristics of CCA, which may lead to better prognosis, drug repurposing and treatment strategies.

• cholangiocarcinoma
• genomic alterations
• metabolites
• omics
• small molecule compounds/drugs

Effective endoscopic management is fundamental for the treatment of extrahepatic cholangiocarcinoma (ECC). However, current biliary stents that are widely used in clinical practice showed no antitumor effect. Drug-eluting stents (DESs) may achieve a combination of local chemotherapy and biliary drainage to prolong stent patency and improve prognosis.

To develop novel DESs coated with gemcitabine (GEM) and cisplatin (CIS)-coloaded nanofilms that can maintain the continuous and long-term release of antitumor agents in the bile duct to inhibit tumor growth and reduce systemic toxicity.

Stents coated with different drug-eluting components were prepared by the mixed electrospinning method, with poly-L-lactide-caprolactone (PLCL) as the drug-loaded nanofiber membrane and GEM and/or CIS as the antitumor agents. Four different DESs were manufactured with four drug-loading ratios (5%, 10%, 15%, and 20%), including bare-loaded (PLCL-0), single-drug-loaded (PLCL-GEM and PLCL-CIS), and dual-drug-loaded (PLCL-GC) stents. The drug release property, antitumor activity, and biocompatibility were evaluated in vitro and in vivo to confirm the feasibility and efficacy of this novel DES for ECC.

The in vitro drug release study showed the stable, continuous release of both GEM and CIS, which was sustained for over 30 d without an obvious initial burst, and a higher drug-loaded content induced a lower release rate. The drug-loading ratio of 10% was used for further experiments due to its ideal inhibitory efficiency and relatively low toxicity. All drug-loaded nanofilms effectively inhibited the growth of EGI-1 cells in vitro and the tumor xenografts of nude mice in vivo; in addition, the dual-loaded nanofilm (PLCL-GC) had a significantly better effect than the single-drug-loaded nanofilms (P < 0.05). No significant differences in the serological analysis (P > 0.05) or histopathological changes were observed between the single-loaded and drug-loaded nanofilms after stent placement in the normal porcine biliary tract.

This novel PLCL-GEM and CIS-eluting stent maintains continuous, stable drug release locally and inhibits tumor growth effectively in vitro and in vivo. It can also be used safely in normal porcine bile ducts. We anticipate that it might be considered an alternative strategy for the palliative therapy of ECC patients.

• Extrahepatic cholangiocarcinoma
• Drug-eluting stent
• Local chemotherapy
• Gemcitabine
• Cisplatin
• Biliary obstruction

• Animals
• Bile Duct Neoplasms/drug therapy
• Bile Ducts, Intrahepatic
• Cholangiocarcinoma/drug therapy
• Cisplatin
• Deoxycytidine/analogs & derivatives
• Drug-Eluting Stents
• Feasibility Studies
• Humans
• Mice
• Mice, Nude
• Stents
• Swine
• Gemcitabine

Histone deacetylase inhibitors (HDACi) have been approved and achieved success in hematologic malignancies. But its application in solid tumors still confronts big challenges and is hampered by low treatment efficacy. Nanotechnology has been widely applied in cancer therapy, and nanomedicine could improve drug stability, prolong the circulation half-life, and increase intratumoral drug accumulation. Therefore, nanomedicine is a promising strategy to enhance HDACi therapy efficacy. The review provides a summary of the advances of HDACi nanomedicines with a focus on the design principles of the targeting delivery systems for HDACi.

• Histone deacetylase inhibitors (HDACi)
• cancer therapy
• combination therapy
• nanomedicine
• nanotechnology
• solid tumor
• targeting drug delivery

• Bile Duct Neoplasms/blood supply
• Bile Duct Neoplasms/drug therapy
• Bile Duct Neoplasms/enzymology
• Cholangiocarcinoma/blood supply
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/enzymology
• Clinical Trials as Topic
• Gene Expression Regulation, Neoplastic/drug effects
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylase Inhibitors/therapeutic use
• Histone Deacetylases/genetics
• Histone Deacetylases/metabolism
• Humans
• Molecular Targeted Therapy
• Prognosis
• Survival Analysis
• Treatment Outcome

• autophagy activation
• autophagy inhibition
• chemoresistance
• cholangiocarcinoma

• Antineoplastic Agents/pharmacology
• Autophagy/drug effects
• Autophagy/genetics
• Autophagy/physiology
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/pathology
• Humans
• Lysosomes/drug effects
• Lysosomes/metabolism
• Signal Transduction/drug effects
• Tumor Microenvironment/drug effects

There is an urgent and unmet need to develop effective therapies for triple negative breast cancers (TNBCs) which are much more aggressive and have poor prognosis due to lack of receptor targets for Her2-targeted and endocrine therapy. In this study we systematically evaluated the effect of Vorinostat (SAHA, a pan-HDAC inhibitor) in reactivating the expression of functional estrogen receptor α (ERα) and synergizing with tamoxifen (TAM, a selective estrogen-receptor modulator) in antitumor activity. In addition, a SAHA prodrug-based dual functional nanocarrier was developed for codelivery of SAHA and TAM for effective combination therapy.

Methods: A SAHA-containing polymeric nanocarrier, POEG-co-PVDSAHA was developed via reversible addition-fragmentation transfer (RAFT) polymerization with SAHA incorporated into the polymer through a redox-responsive disulfide linkage. The effect of both free SAHA and POEG-co-PVDSAHA on reactivating the expression of functional ERα was investigated in several human and murine TNBC cell lines via examining the mRNA and protein expression of ERα target genes. The cytotoxicity of free SAHA and TAM combination and TAM-loaded POEG-co-PVDSAHA micelles was examined via MTT assay. The in vivo antitumor activity of TAM-loaded POEG-co-PVDSAHA was investigated in a murine breast cancer model (4T1.2).

Results: Both free SAHA and POEG-co-PVDSAHA were effective in inducing the reexpression of functional estrogen receptor α (ERα), which may have helped to sensitize TNBCs to TAM. More importantly, POEG-co-PVDSAHA self-assembled to form small-sized micellar carrier that is effective in formulating and codelivery of TAM. TAM-loaded POEG-co-PVDSAHA micelles exhibited enhanced and synergistic cytotoxicity against TNBC cell lines compared with free SAHA, free TAM and TAM loaded into a pharmacologically inert control carrier (POEG-co-PVMA). In addition, codelivery of TAM via POEG-co-PVDSAHA micelles led to significantly improved antitumor efficacy in 4T1.2 tumor model compared with other groups such as combination of free SAHA and TAM and TAM-loaded POEG-co-PVMA micelles.

Conclusion: Our prodrug-based co-delivery system may provide an effective and simple strategy to re-sensitize TNBCs to TAM-based hormone therapy.

• co-delivery
• prodrug micelles
• redox responsive
• tamoxifen
• vorinostat

• asbestos
• cancer
• epigenetic
• histone deacetylases
• inhibitors
• nanoparticles
• ring-opening metathesis polymerization

Hybrid mesoporous nanorods with six twisted sharp edges can induce effective penetration of intracellular barriers and cytosolic delivery of membrane-impermeable drugs through curvature effects.

• core cross-linked nanoparticle
• diselenium
• pH responsive
• reactive oxygen species
• redox responsive

• A549 Cells
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Chitosan/analogs & derivatives
• Chitosan/chemistry
• Colorectal Neoplasms/drug therapy
• Dioxolanes/chemistry
• Dioxolanes/pharmacology
• Drug Carriers/chemistry
• Drug Delivery Systems/methods
• Humans
• Hydrogen-Ion Concentration
• Lung Neoplasms/drug therapy
• Nanoparticles/administration & dosage
• Nanoparticles/chemistry
• Oxidation-Reduction
• Polyethylene Glycols/chemistry

• Biliary tract cancer
• gene mutations
• stromal microenvironment
• tumor biomarker

• Biliary tract
• Cholangiocarcinoma
• Dysregulation
• Epigenetics
• Epigenome

• Adult
• Cell Differentiation/genetics
• Chemoradiotherapy/adverse effects
• Cholangiocarcinoma/classification
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/pathology
• Humans
• Liver Neoplasms/classification
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Transplantation/trends
• Molecular Targeted Therapy
• Neoadjuvant Therapy
• Precision Medicine
• Prognosis

• P30 DK084567 NIDDK NIH HHS
• R01 DK059427 NIDDK NIH HHS
• R03 CA212877 NCI NIH HHS
• R56 DK059427 NIDDK NIH HHS

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.

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.

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.

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.

• GI stent
• cholangiocarcinoma
• drug eluting
• nanofiber
• vorinostat

Cholangiocarcinoma (CCA) is a rare cancer arising from the biliary tree with a poor prognosis and limited therapeutic options. Recent large scale molecular characterisation studies have identified recurrent genetic alterations in CCA which may be amenable to therapeutic targeting. In this review we explore the genomic landscape of CCA and examine results from trials of molecularly targeted agents and immunotherapy in this disease. Challenges in CCA diagnosis, treatment and trial design are discussed and we reflect on future directions which may lead to improved outcomes for CCA patients.

• Cholangiocarcinoma
• Biliary tract cancer
• Targeted therapy
• Immunotherapy
• Mutation
• Molecular
• Microenvironment
• Stroma
• MiRNA

• SAHA
• anticancer
• drug delivery
• in vivo efficacy
• polymeric micelles

• ARID1A
• FGFR2
• Next-generation sequencing (NGS)
• biliary tract cancers (BTCs)
• isocitrate dehydrogenase 1 or 2 (IDH1/2)
• overall survival
• targeted therapy