Fabrication IL-1Ra loaded galactosylated chitosan nanoparticles for liver targeting

Galactosylated chitosan （GC） is synthesized and used to prepare IL-1Ra loaded GC nanoparticles by an electrospraying technique. Polyethylene oxide （PEO） is mixed with GC to enhance the electrospraying ability. The effect of the spraying solution properties on particle formation is investigated. The IL-1Ra loaded nanoparticles with an average diameter of 530 nm and a regularly spherical shape are observed by the scanning electron microscopy （SEM）. The amount of the IL-1Ra is measured by the enzyme-linked immunosorbent assay （ELISA） kit. The loading capacity of the nanoparticle is （1.52± 0.04）% （n = 3） and the encapsulation efficiency reaches （90. 36 ± 3.46） % （n = 3）. For the evaluation of GC nanoparticles＇ hepatocytes targeting efficacy, hepatocytes and mesenchymal stem cells （MSCs） are incubated with FITC-labeled GC nanoparticles for 24 h as the experimental and control groups. Results of the fluorescence microscope show that the fluorescence signals observed in hepatocytes are significantly higher than in the MSCs, indicating that the developed GC nanoparticles have an obvious liver targeting property.

Study on liver targeting and hepatocytes permeable valaciclovir polybutylcyanoacrylate nanoparticles *

AIM To prepare valaciclovir polybutylcyan_ oacrylate nanoparticles (VACV PBCA NP) with liver targeting and hepatocyte permeable characteristics. METHODS Emulsion polymerization method was employed to prepare VACV PBCA NP. The formula and preparation conditions were optimized by using the uniform design. The organ distribution of the intravenously injected VACV PBCA NP and VACV in animal was determined using HPLC. The hepatocytes permeability of VACV PBCA NP was demonstrated by cell uptake experiment in vitro . RESULTS The drug loading and the drug embedding ratio of VACV PBCA NP were 11 20% and 84 85% respectively, with an average diameter of 104 77nm ± 11 78nm . The releasing characteristics in vitro fitted the two phase kinetics. 74 49% of the drug was found to localize in the liver 15min after the administration of VACV PBCA NP in the mice. Compared with VACV, VACV PBCA NP showed distinct characteristic of sustained release in vivo and the drug entering hepatocytes were also greatly increased. CONCLUSION VACV PBCA NP has the char_ acteristic of liver targeting and can increase the permeability of VACV to hepatocytes.

In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting

The objective of this study was to prepare cubosomal nanoparticles containing a hydrophilic anticancer drug 5-fluorouracil(5-FU) for liver targeting. Cubosomal dispersions were prepared by disrupting a cubic gel phase of monoolein and water in the presence of Poloxamer 407 as a stabilizer.Cubosomes loaded with 5-FU were characterized in vitro and in vivo. In vitro, 5-FU-loaded cubosomes entrapped 31.21% drug and revealed nanometer-sized particles with a narrow particle size distribution. In vitro 5-FU release from cubosomes exhibited a phase of rapid release of about half of the entrapped drug during the first hour, followed by a relatively slower drug release as compared to 5-FU solution. In vivo biodistribution experiments indicated that the cubosomal formulation significantly(Po 0.05) increased5-FU liver concentration, a value approximately 5-fold greater than that observed with a 5-FU solution.However, serum serological results and histopathological findings revealed greater hepatocellular damage in rats treated with cubosomal formulation. These results demonstrate the successful development of cubosomal nanoparticles containing 5-FU for liver targeting. However, further studies are required to evaluate hepatotoxicity and in vivo antitumor activity of lower doses of 5-FU cubosomal formulation in treatment of liver cancer.

Curcumin delivery nanoparticles based on Maillard reaction of Haematococcus pluvialis protein/galactose for alleviating acute alcoholic liver damage

The aim of this study is to investigate the feasibility of Maillard reaction products of Haematococcus pluvialis protein and galactose(HPP-GAL)for improving the bioactivities of curcumin(CUR)for alleviating alcoholic liver damage.CUR was embedded into HPP-GAL nanoparticles by the self-assembly of hydrogen bonding and hydrophobic interaction with the particle size around 200 nm.HPP-GAL enhanced the encapsulation efficiency and loading amount of CUR with the value of(89.21±0.33)%and(0.500±0.004)%,respectively.The stabilities of CUR under strong acid,salt ion stability and ultraviolet irradiation conditions were improved by the encapsulation.HPP-GAL-CUR nanoparticles exhibited excellent concentration-dependent in vitro antioxidant activities including DPPH and ABTS scavenging rates,and better protective effect on CUR against gastric acid environment as well as longer release of CUR in simulated intestinal fluid.In addition,the HPPGAL-CUR delivery system possessed liver targeting property due to the existence of GAL,which could effectively alleviate the alcohol-induced liver damage and the inflammation indexes by inhibiting the oxidative stress.Therefore,HPP-GAL-CUR nanoparticles might be a potential candidate system for the prevention of alcoholic liver damage in the future.

Cytotoxicity of liver targeted drug-loaded alginate nanoparticles

In this study, novel liver targeted doxorubicin (DOX) loaded alginate (ALG) nanoparticles were prepared by CaCl2 crosslinking method. Glycyrrhetinic acid (GA, a liver targeted molecule) modified alginate (GA-ALG) was synthesized in a heterogeneous system, and the structure of GA-ALG and the substitu-tion degree of GA were analyzed by 1H NMR, FT-IR and elemental analysis. The drug release profile under the simulated physiological condition and cytotoxicity experiments of drug-loaded GA-ALG nanoparticles were carried out in vitro. Transmission electron micrographs (TEM) and dynamic light scattering (DLS) analysis showed that drug-loaded GA-ALG nanoparticles have spherical shape structure with the mean hydrodynamic diameter around 214 ± 11 nm. The drug release was shown to last 20 days, and the MTT assay suggested that drug-loaded GA-ALG nanoparticles had a distinct kill-ing effect on 7703 hepatocellular carcinoma cells.

Autophagy:A new therapeutic target for liver fibrosis

Hepatic fibrosis is a wound-healing response to liver injury and the result of imbalance of extracellular matrix(ECM) accumulation and degradation. The relentlessproduction and progressive accumulation of ECM can lead to end-stage liver disease. Although significant progress has been achieved in elucidating the mechanisms of fibrogenesis, effective anti-fibrotic strategies are still lacking. Autophagy is an intracellular process of self-digestion of defective organelles to provide material recycling or energy for cell survival. Autophagy has been implicated in the pathophysiology of many human disorders including hepatic fibrosis. However, the exact relationships between autophagy and hepatic fibrosis are not totally clear and need further investigations. A new therapeutic target for liver fibrosis could be developed with a better understanding of autophagy.

MicroRNAs and liver cancer associated with iron overload:Therapeutic targets unravelled

Primary liver cancer is a global disease that is on the increase.Hepatocellular carcinoma(HCC)accounts for most primary liver cancers and has a notably low survival rate,largely attributable to late diagnosis,resistance to treatment,tumour recurrence and metastasis.MicroRNAs(miRNAs/miRs)are regulatory RNAs that modulate protein synthesis.miRNAs are involved in several biological and pathological processes including the development and progression of HCC.Given the poor outcomes with current HCC treatments,miRNAs represent an important new target for therapeutic intervention.Several studies have demonstrated their role in HCC development and progression.While many risk factors underlie the development of HCC,one process commonly altered is iron homeostasis.Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised.Aberrant miRNA expression in hepatic fibrosis and injury response have been reported,as have dysregulated miRNA expression patterns affecting cell cycle progression,evasion of apoptosis,invasion and metastasis.In2009,miR-26a delivery was shown to prevent HCC progression,highlighting its therapeutic potential.Several studies have since investigated the clinical potential of other miRNAs with one drug,Miravirsen,currently in phaseⅡclinical trials.miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy.Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years,yielding improved HCC survival rates and patient outcomes.

MicroRNA-216a: a potential therapeutic target for drug resistance and recurrent of liver cancer

The Editor welcomes submissions for possible publication in the Letters to the Editor section.Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are received within 6 weeks of the time the article was published.Authors of the article being commented on will be given an opportunity to offer a timely response to the letter.Authors of letters will be notified that the letter has been received.Unpublished letters cannot be returned.

Liver-specific drug delivery platforms: Applications for the treatment of alcohol-associated liver disease

Alcohol-associated liver disease(ALD)is a common chronic liver disease and major contributor to liver disease-related deaths worldwide.Despite its prevalence,there are few effective pharmacological options for the severe stages of this disease.While much pre-clinical research attention is paid to drug development in ALD,many of these experimental therapeutics have limitations such as poor pharmacokinetics,poor efficacy,or off-target side effects due to systemic administration.One means of addressing these limitations is through liver-targeted drug delivery,which can be accomplished with different platforms including liposomes,polymeric nanoparticles,exosomes,bacteria,and adenoassociated viruses,among others.These platforms allow drugs to target the liver passively or actively,thereby reducing systemic circulation and increasing the‘effective dose’in the liver.While many studies,some clinical,have applied targeted delivery systems to other liver diseases such as viral hepatitis or hepatocellular carcinoma,only few have investigated their efficacy in ALD.This review provides basic information on these liver-targeting drug delivery platforms,including their benefits and limitations,and summarizes the current research efforts to apply them to the treatment of ALD in rodent models.We also discuss gaps in knowledge in the field,which when addressed,may help to increase the efficacy of novel therapies and better translate them to humans.

Overview of organic anion transporters and organic anion transporter polypeptides and their roles in the liver

Organic anion transporters(OATs)and organic anion transporter polypeptides(OATPs)are classified within two SLC superfamilies,namely,the SLC22A superfamily and the SLCO superfamily(formerly the SLC21A family),respectively.They are expressed in many tissues,such as the liver and kidney,and mediate the absorption and excretion of many endogenous and exogenous substances,including various drugs.Most are composed of 12 transmembrane polypeptide chains with the C-terminus and the N-terminus located in the cell cytoplasm.OATs and OATPs are abundantly expressed in the liver,where they mainly promote the uptake of various endogenous substrates such as bile acids and various exogenous drugs such as antifibrotic and anticancer drugs.However,differences in the locations of glycosylation sites,phosphorylation sites,and amino acids in the OAT and OATP structures lead to different substrates being transported to the liver,which ultimately results in their different roles in the liver.To date,few articles have addressed these aspects of OAT and OATP structures,and we study further the similarities and differences in their structures,tissue distribution,substrates,and roles in liver diseases.

Current treatment options for patients with initially unresectable isolated colorectal liver metastases

The development of liver metastases is a common clinical entity in the clinical course of colorectal cancer. For patients with isolated liver involvement, surgical resection is the only treatment that can provide a chance of prolonged survival and cure. However, most of these patients are not initially eligible for the surgery. Selected patients with initially considered to have unresectable disease may become resectable after systemic(che-motherapy ± biological therapy) and loco-regional treatment modalities including hepatic arterial infusion. Patients who have colorectal liver metastases ideally should be referred to a multidisciplinary cancer care team in order to identify the most optimal management approach.

An update on chemotherapy of colorectal liver metastases

Surgical resection of liver metastases of colorectal cancer greatly improves the clinical outcome of patients with advanced disease. Developments in chemotherapeutic agents and strategies bring hope of a cure to patients with initially unresectable colorectal liver metastases (CLM). Perioperative chemotherapy signif icantly improves the survival time of patients who receive curative-intent hepatectomy. Even for unresectable CLM, recent studies demonstrated that active preoperative chemotherapy could achieve shrinkage of liver metastasis and thus render some for resection. Furthermore, an increase in tumor resection rate and prolonged survival time among patients with CLM has been observed following the application of monoclonal antibodies in recent years. However, the value of chemotherapy via hepatic arterial infusion is still unclear. More trials should be conducted in patients with CLM in order to improve survival.

Management of recurrent hepatocellular carcinoma after liver transplant

Hepatocellular carcinoma(HCC) is the leading cause of deaths in patients with hepatitis B or C, and its incidence has increased considerably over the past decade and is still on the rise. Liver transplantation(LT) provides the best chance of cure for patients with HCC and liver cirrhosis. With the implementation of the MELD exception system for patients with HCC waitlisted for LT, the number of recipients of LT is increasing, so is the number of patients who have recurrence of HCC after LT. Treatments for intrahepatic recurrence after transplantation and after other kinds of surgery are more or less the same, but long-term cure of posttransplant recurrence is rarely seen as it is a "systemic" disease. Nonetheless, surgicalresection has been shown to be effective in prolonging patient survival despite the technical difficulty in resecting graft livers. Besides surgical resection, different kinds of treatment are also in use, including transarterial chemoembolization, radiofrequency ablation, highintensity focused ultrasound ablation, and stereotactic body radiation therapy. Targeted therapy and modulation of immunosuppressants are also adopted to treat the deadly disease.

Glyco-poly-L-lysine is better than liposomal delivery of exogenous genes to rat liver

AIM To compare the effects of liposomes andglyco-poly-L-lysine on liver targeted uptake andexpression of plasmid in rat liver.METHODS After binding with lipofectamine orgalactose-terminal glyco-poly-L-lysine,theplasmid could be expressed in eukaryotic cellswhen injected into Wistar rats by intravenousroute.At different time intervals after the injection,the distribution and expression of the plasmid inliver of rats were observed and compared using insitu hybridization and immunohistochemistry.RESULTS The expression of the plasmid bindingto liposomes or G-PLL could be markedly observed24 h later,and began to decrease one week later,but it still could be observed up to three weeks.Both liposomes and G-PLL could deliver theplasmid to the liver effectively,but the effect of thelatter was better than the former concerning thedistribution and expression of the plasmid targeteduptake in the liver.CONCLUSION G-PLL is better than liposome asthe targeted carrier for delivering exogenous genesto the liver.

Sirolimus plus sorafenib in treating HCC recurrence after liver transplantation: A case report

A case of hepatocellular carcinoma (HCC) with pulmonary recurrence after liver transplantation for HCC is presented in this report. The patient showed disease progression on sorafenib therapy demonstrated by computed tomography scans as well as serial serum α-fetoprotein (AFP) elevation. After his immunosuppression therapy was successfully transitioned to sirolimus and a continuation of sorafenib, he achieved partial remission based on RECIST criteria and normalization of AFP. Mammalian target of rapamycin inhibitors including sirolimus alone or in conjunction with sorafenib may be useful in the treatment of post transplant HCC.

Role of microRNA in liver regeneration

BACKGROUND： Liver regeneration is a complex process. micro RNAs（mi RNAs） are short, single-stranded RNAs that modify gene expression at the post-transcriptional level. Recent investigations have revealed that mi RNAs are closely linked to liver regeneration.DATA SOURCES： All included studies were obtained from Pub Med, Embase, the Science Direct databases and Web of Science, with no limitation on publication year. Only studies published in English were considered.RESULTS： We grouped studies that involved mi RNA and liver regeneration into two groups： mi RNAs as promoters and as inhibitors of liver regeneration. We summarized the relevant mi RNAs separately from the related pathways.CONCLUSIONS： Blocking or stimulating the pathways of mi RNAs in liver regeneration may be novel therapeutic strategies in future regeneration-related liver managements. We may discover additional chemotherapy targets of mi RNA.

Role of spleen tyrosine kinase in liver diseases

Spleen tyrosine kinase (SYK),a non-receptor tyrosine kinase,is expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses.SYK mediate diverse cellular responses via an immune-receptor tyrosine-based activation motifs (ITAMs)-dependent signalling pathways,ITAMs-independent and ITAMs-semidependent signalling pathways.In liver,SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells) and found to be positively correlated with the disease severity.The implication of SYK pathway has been reported in different liver diseases including liver fibrosis,viral hepatitis,alcoholic liver disease,non-alcoholic steatohepatitis and hepatocellular carcinoma.Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target.This review summarizes the current understanding of SYK and its therapeutic implication in liver diseases.

Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients

AIM: To evaluate the expression of serum fibrosis markers in liver transplantation(LT) recipients on everolimus monotherapy compared to patients on an anti-calcineurin regimen.METHODS: This cross-sectional case-control study included LT patients on everolimus monotherapy(cases)(E)(n = 30) and matched controls on an anticalcineurin regimen(calcineurin inhibitors, CNI), paired by etiology of liver disease and time since LT(n = 30). Clinical characteristics, blood tests and elastography were collected. Serum levels of transforming growth factor-β(TGF-β), angiopoietin-1, tumor necrosis factor(TNF), platelet derived growth factor, amino-terminal propeptide of type Ⅲ procollagen(PⅢNP), hyaluronicacid(HA), VCM-1(ng/m L), interleukin(IL)-10, interferoninducible protein 10(IP-10), vascular endothelial growth factor and hepatocyte growth factor(HGF)(pg/m L) were determined by enzyme-linked immunosorbent assay. Expression of these markers between E and CNI was compared. Stratified analysis was done according to factors that may influence liver fibrosis. Variables are described with medians(interquartillic range) or percentages.RESULTS: A total of 60 patients [age: 59(49-64), hepatitis C virus(HCV): n = 21(35%), time from LT: 73 mo(16-105)] were included. Patients had been on everolimus for a median of 15 mo. No differences in inflammatory activity, APRI test or liver elastography were found between the groups. No significant differences were observed between the groups in serum levels of PⅢ NP, metalloproteinase type = 1, angiopoietin, HGF, IP-10, TNF-α, IL-10 and vascular cell adhesion molecule. Patients on E had a lower expression of TGF-β [E: 12.7(3.7-133.6), CNI: 152.5(14.4-333.2), P = 0.009] and HA [E: 702.89(329.4-838.2), CNI: 1513.6(691.9-1951.4), P = 0.001] than those on CNI. This difference was maintained in the stratified analysis when recipient age is more than 50 years(TFG-β1: P = 0.06; HA: P = 0.005), in patients without active neoplasia(TFG-β1, P = 0.009; HA: P = 0.01), according to time since LT(> than 5 years, TFG-β1: P = 0.001; HA: P = 0.002), related to previous history of biliary complications(HA: P = 0.01) and HCV recurrence(HA: P = 0.004). Liver transplant recipients with everolimus monotherapy had less serum expression of TGF-β y HA than matched patients with anti-calcineurins. This difference remains when classifying patients according to donor age and time since LT. Due to the small sample size, when examining patients with a prior history of biliary complications or recurrent HCV, the difference was nonsignificant but trends towards the lower expression of TFG-β1 in the everolimus group. Mammalian target of rapamycin(m TOR) plays a role in the transformation of quiescent hepatocellular stellate cell to their activeprofibrotic state, and experimental models have demonstrated the potential activity of m TOR inhibition in attenuating fibrogenesis.CONCLUSION: This study supports a possible role of everolimus in liver fibrosis modulation after LT in a clinical setting and suggests that tailoring immunosuppression could avoid fibrosis progression in the allograft.

Management of potentially resectable colorectal cancer liver metastases

Colorectal cancer is a very common malignancy worldwide and development of liver metastases,both synchronous or metachronous,is a common event.Of all patients with metastatic colorectal cancer,up to 77% have a liver-only disease and approximately 10%-20% of patients with colorectal liver metastases are considered resectable at the time of diagnosis.Surgical resection of liver metastases remains the best treatment option and it is associated with a survival plateau and a 20%-25% of long-term survivors.Perioperative chemotherapy for resectable liver metastases may improve resecability of liver metastases and disease free survival,but its impact on overall survival is still unclear and more studies are needed.Moreover,preoperative chemotherapy can increase postoperative complications.Further studies are needed to define the role of adjuvant chemotherapy after a R0 resection of liver metastases and to define the criteria for a better selection of patients candidate to hepatectomy.New strategies such as targeted therapies are emerging with promising results.Optimal management requires a multidisciplinary approach,local and systemic,but it is a still pending question.Colorectal liver metastases represent a major challenge for oncologists and surgeons.In this review will be analyzed available data about assessment and management of the patients with potentially resectable colorectal liver metastases.

Conversion from calcineurin inhibitors to mTOR inhibitors stabilizes diabetic and hypertensive nephropathy after liver transplant

AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors(mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine.METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation(OLT), including all liver recipients with worsening renal function before conversion to mTORi(n = 55 patients) and recipients with normal renal function who converted to m TORi for other reasons(n = 31 patients). We identified patients with diabetes mellitus(n = 28), arterial hypertension(n = 27), proteinuria(n = 27) and all three factors(n = 8)(some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus(DM), hypertension(HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction.RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function(2.14 to 1.77 mg/dL)(P = 0.02). Patients with DM showed no improvement of serum creatinine levels(1.31 mg/dL to 1.37 mg/dL) compared with non DM patients(1.31 mg/dL to 1.15 mg/dL)(P = 0.01), HT patients(1.48 mg/dL to 1.5 mg/dL) with non HT patients(1.21mg/d L to 1.08 mg/dL) and patients with proteinuria(1.44 mg/dL to 1.41 mg/dL) and no proteinuria(1.31 mg/dL to 1.11 mg/dL). CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to m TORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to m TORi; it also stabilizes renal function. Conversion to m TORi should only be avoided in patients with diabetes, hypertension and proteinuria.