iRGD-modified sterically stabilized liposomes loaded doxorubicin (iRGD-SSL-DOX) were prepared and their cellular toxicity and anti-tumor efficacy were evaluated, comparing to doxorubixin loaded sterically stabilized liposomes (SSL-DOX) and RGD modified doxorubixin loaded sterically stabilized liposomes (RGD-SSL-DOX). The iRGD peptide, with both tumor targeting and cell penetrating functions, was conjugated to DSPE-PEG-NHS and DSPE-PEG-iRGD was obtained. DSPE-PEG-RGD was gained in the same way. iRGD-SSL-DOX, RGD-SSL-DOX and SSL-DOX were prepared by ammonium sulfate gradient method. The size and zeta potential of the liposomes were characterized by dynamic laser light scattering. The cellular toxicity study was done on B16 melanoma cell line and the anti-tumor efficacy study was carried on B16 cell line bearing C57BL/6 mice. The results showed that the particle sizes of liposomes were all around 90-100 nm. DOX entrapment efficiency was above 95%. The formulations were with good preparation reproducibility. iRGD-SSL-DOX showed no significant difference in B16 cellular toxicity with SSL-DOX and RGD-SSL-DOX, but the anti-tumor efficacy on B16 melanoma bearing C57BL/6 mice was significantly better than that of SSL-DOX, similar as that of RGD-SSL-DOX. Therefore, iRGD modified liposomes loaded DOX would be a promising drug delivery system for tumor therapy.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Doxorubicin ; administration & dosage ; pharmacology ; Drug Carriers ; Drug Delivery Systems ; Liposomes ; Male ; Melanoma, Experimental ; pathology ; Mice ; Mice, Inbred C57BL ; Molecular Weight ; Neoplasm Transplantation ; Oligopeptides ; chemistry ; pharmacology ; Particle Size ; Phosphatidylethanolamines ; chemistry ; Polyethylene Glycols ; chemistry ; Tumor Burden ; drug effects

To investigate the rat intestinal absorption of stearic acid-octaarginine (SA-R8) modified solid lipid nanoparticles containing paclitaxel (SA-R8-PTX-SLN), compared with the commercially available preparation of PTX (Taxol) and PTX-loaded solid lipid nanoparticles (PTX-SLN), the in situ intestinal absorption of SA-R8-PTX-SLN was investigated by means of single-pass rat intestinal perfusion technique. The absorptions of the preparations were investigated at different intestinal segments, different drug concentrations and in the presence of P-glycoprotein inhibitor (verapamil). The results showed that PTX could be absorbed at each intestinal segment and the three preparations all showed maximum absorptions at the duodenum. The cumulative absorptions of three preparations at each intestinal segment appeared SA-R8-PTX-SLN > PTX-SLN > Taxol (P < 0.05). SA-R8-PTX-SLN showed a liner absorption manner at the duodenum in the examined drug concentration range. The cumulative absorptions of Taxol and PTX-SLN were significantly promoted after the addition of P-glycoprotein inhibitor (verapamil) into the preparation (P < 0.05), but absorption of SA-R8-PTX-SLN existed no significantly difference compared with the preparation without verapamil (P > 0.05). SA-R8 and SLN might both effectively improve the oral absorption of PTX in the intestinal tract.
ATP-Binding Cassette, Sub-Family B, Member 1 ; antagonists & inhibitors ; Animals ; Antineoplastic Agents, Phytogenic ; administration & dosage ; chemistry ; pharmacokinetics ; Cell-Penetrating Peptides ; chemistry ; Drug Carriers ; Intestinal Absorption ; drug effects ; Lipids ; chemistry ; Male ; Nanoparticles ; Oligopeptides ; chemistry ; Paclitaxel ; administration & dosage ; chemistry ; pharmacokinetics ; Perfusion ; Rats ; Rats, Sprague-Dawley ; Stearic Acids ; chemistry ; Verapamil ; pharmacology

OBJECTIVETo evaluate the efficacy and safety of telaprevir combined with peginterferon alfa (Peg-IFNa) plus ribavirin (RBV) (collectively, TPR therapy) in patients with chronic hepatitis C (CHC) using a meta-analysis approach.

METHODSThe Pubmed literature database was searched for randomized controlled trials of TRP therapy in CHC patients published between 2009 and 2011. The following outcome data was extracted for meta-analysis of efficacy: sustained virological response (SVR), defined as serum HCV RNA of less than 1000 copies/ml at end-of-treatment (week 24); rapid virological response (RVR), defined as serum HCV RNA of less than 1000 copies/ml at treatment week 4; recurrence, defined as serum HCV RNA of less than 1000 copies/mL at end-of-treatment and more than 1000 copies/ml at follow-up (week 24 after treatment completion). The pooled odds ratio (OR) or relative risk (RR) were calculated, with 95% confidence interval (CI). Heterogeneity was assessed by the Chi-squared test based on the Q statistic.

RESULTSSix studies of TPR triple therapy, representing a total of 2677 CHC patients, were included in the meta-analysis. Among the 1850 patients who received TPR, 56.3% (n = 1041) achieved RVR, 66.8% (n = 1235) achieved SVR, and 12.1% (n = 176/1460) experienced recurrence. Among the 827 patients who received PR double-therapy, 7.0% (n = 58) achieved RVR, 35.8% (n = 296) achieved SVR, and 32.3% (n = 145/449) experienced recurrence. The TRP group had significantly higher rates of RVR (OR = 29.83, 95% CI: 16.16 to 55.05) and SVR (OR = 3.97, 95% CI: 2.58 to 6.11) than the PR group (both P less than 0.01), and significantly lower rate of recurrence (RR = 0.36, 95% CI: 0.24 to 0.56, P less than 0.01).

CONCLUSIONThe therapeutic effect of research group is better than that of control group, suggesting that ornithine aspartate combined with naloxone treatment in hepatic encephalopathy is worthy of promoting.

Drug Therapy, Combination ; Hepatitis C, Chronic ; drug therapy ; Humans ; Interferon-alpha ; administration & dosage ; therapeutic use ; Oligopeptides ; administration & dosage ; therapeutic use ; Ribavirin ; administration & dosage ; therapeutic use ; Treatment Outcome

Aspargine-glycine-arginine (NGR)-containing peptides are targeted peptides which can be integrated with CD13 receptors on tumor vascular endothelial cells. NGR peptides are connected to liposomes to obtain NGR peptide-modified liposomes. By intravenous injection of these liposomes, NGR peptides can be combined with CD13 receptors on tumor vascular endothelial cells, position liposomes in tumor tissues, and concentrate drug in liposomes in tumor, so as to enhance the antitumor effect. The article starts with NGR peptides, summarizes definition of NGR, NGR peptide-modified liposomes, strengths and weaknesses of NGR peptide-modified liposomes in antitumor and the latest study orientation of NGR peptide-modified liposomes, and looks into the future of studies on NGR peptide-modified liposomes.
Animals ; Antineoplastic Agents ; pharmacology ; CD13 Antigens ; administration & dosage ; pharmacology ; Humans ; Liposomes ; Oligopeptides ; administration & dosage ; pharmacology

The hydroxycamptothecin (HCPT) PEGylated liposomes (HCPT-LP) were modified with RGD cyclopeptide formed the tumor-targeting liposomes (HCPT-RGD-LP). HCPT-LP and HCPT-RGD-LP were injected intravenously with single dose of 5 mg x kg(-1) to rats. The drug concentration in plasma was determined and the pharmacokinetic behaviour was compared. The HCPT distribution in heart, liver, spleen, lung, kidney and plasma of mice was investigated following intravenous administration of HCPT-LP and HCPT injection. The nude mice implanted human hepatoma HepG2 cells were studied by in vivo imaging. The fluorescent probe was DiR and the nude mice were injected with DiR PEGylated liposomes (DiR-LP) and DiR-LP modified with RGD cyclopeptide (DiR-RGD-LP). The results showed that there was no significant difference (P > 0.05) of main pharmacokinetic parameters t1/2beta, CL, V(c), AUC(0-48 h), AUC(0-inifinity), MRT(0-48 h), MRT(0-infinity) between HCPT-RGD-LP and HCPT-LP. HCPT-LP had a remarkably better long-circulating effect than HCPT injection in mice and the concentration of HCPT was highest in liver. The DiR accumulation in tumors of DiR-RGD-LP was higher than that of DiR-LP by the visualized fluorescence of in vivo imaging. It indicated that such PEGylated liposomes modified with RGD cyclopeptide could improve the tumor targeting efficacy.
Animals ; Area Under Curve ; Camptothecin ; administration & dosage ; analogs & derivatives ; chemistry ; pharmacokinetics ; Diagnostic Imaging ; Drug Delivery Systems ; Female ; Fluorescent Dyes ; Hep G2 Cells ; Humans ; Liposomes ; administration & dosage ; chemistry ; pharmacokinetics ; Liver Neoplasms ; diagnosis ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Oligopeptides ; administration & dosage ; chemistry ; pharmacokinetics ; Polyethylene Glycols ; administration & dosage ; chemistry ; pharmacokinetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spectroscopy, Near-Infrared ; Tissue Distribution

A novel synthetic hexapeptide (SFKLRY-NH2) that displays angiogenic activity has been identified by positional scanning of a synthetic peptide combinatorial library (PS-SPCL). This study was carried out to investigate the irritation of the SFKLRY-NH2 on the skin. The tests were performed on the basis of Korea Food and Drug Administration (KFDA) guidelines. In results, cell toxicity is not appeared for SFKLRY-NH2 in HaCaT cells and B16F10 cells. SFKLRY-NH2 induced no skin irritation at low concentration (10 microM), mild irritation at high concentration (10mM). We consider that this result is helpful for saying about the safety of SFKLRY-NH2 in clinical use.
Korea ; Oligopeptides ; Peptide Library ; Skin ; United States Food and Drug Administration

PURPOSE: Serious acetaminophen (AAP) poisoning causes hepatotoxicity. N-acetylcysteine (NAC) is the most effective therapy for AAP poisoning and can be administered orally and intravenously (IV). Several studies have compared the efficacy of these two routes of administration and the results have been controversial. The purpose of this study was to compare the efficacy of oral and IV NAC for the prevention of hepatic toxicity in Korean patients whose serum AAP levels were higher than normal. METHODS: A retrospective before/after study was performed, in which the patients presented to the emergency department with an AAP overdose from February 1995 to March 2012. A 3-day oral NAC regimen was used in the beginning, and a 20-hr intravenous regimen was then used from 2007. This study assessed the complications of an AAP overdose, such as hepatotoxicity, hepatic failure and renal failure as well as the side effects of the treatment regimen. RESULTS: A total of 41patients was enrolled in this study. The median ALT and AST were 63 (IU/L) and 57 (IU/L) for the oral NAC treated patients, and 14 (IU/L) and 20 (IU/L) for the IV NAC treated patients (p=0.004 and p=0.001, respectively). The incidence of complications was similar in the treatment groups (p=0.399). Among the patients, 7 patients developed hepatotoxicity and were treated successfully with oral or IV NAC. CONCLUSION: This study suggests that IV NAC and oral NAC can prevent and successfully treat hepatic toxicity in patients whose serum AAP levels are higher than normal.
Acetaminophen ; Acetylcysteine ; Administration, Intravenous ; Emergencies ; Humans ; Incidence ; Liver Failure ; Oligopeptides ; Renal Insufficiency ; Retrospective Studies

A novel fibrinolytic enzyme subtilisin FS33, which exhibits much higher activity for decomposing fibrin than urokinase, was purified from Douchi, a traditional soybean-fermented food in China. In order to increase bio-utilization and thrombus targetability of subtilisin FS33 labeled by fluorescein isothiocyanate (FITC), the surface modified liposomes encapsulating subtilisin FS33 and FITC with a synthetic peptide Arg-Gly-Asp-Ser (RGDS), being putatively a specific antagonist of fibrinogen receptor on platelet membrane, were prepared and used to evaluate the therapeutic efficacy in a rat model thrombotic carotid artery. The arterial thrombosis was induced by applying two pieces of filter paper (1 x 2 cm) saturated with 10% of ferric chloride (FeCl3). The rats were infused via the jugular vein with either liposomes carrying BSA (control group) or RGDS-liposomes carrying subtilisin FS33 at doses of 2000 and 4000 U/kg. The plasma of the group infused with RGDS-liposomes showed higher antithrombotic and fibrinolytic activity than did the control group within 15-120 min after infusing. The higher the dose was gived, the higher the activity was shown. APTT(activiated partial thromboplastin time), PT (prothrombin time) and TT (thrombin time) were extended remarkably (P < 0.05, P < 0.01), and FDP (fibrinogen degradation products) also increased greatly (P < 0.01), while ELT (euglobulinlysis time) decreased obviously (P < 0.05). FITC content in heart and brain evidently increased (P < 0.05), and results of D-dimer test were all positive. In addition, the venous thrombi in brain and kidney were dissolved totally or partly as observed by patholgical section. All these indicated that subtilisin FS33 enhanced the antithrombotic and fibrinolytic activities in rat, and RGDS-liposomes improved, in a certain degree, the thrombolytic specificity for targeting to thrombus.
Animals ; Carotid Artery Thrombosis ; drug therapy ; etiology ; Drug Carriers ; Drug Delivery Systems ; Female ; Fibrinolytic Agents ; administration & dosage ; Liposomes ; administration & dosage ; chemistry ; Male ; Oligopeptides ; administration & dosage ; chemistry ; Random Allocation ; Rats ; Rats, Wistar ; Subtilisins ; administration & dosage ; isolation & purification

Carcinoma, Hepatocellular ; metabolism ; pathology ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Enzyme Activation ; drug effects ; Flow Cytometry ; Hep G2 Cells ; Humans ; Oligopeptides ; administration & dosage ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Receptor, PAR-2 ; agonists ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Trypsin ; administration & dosage ; pharmacology ; Up-Regulation ; drug effects

Using a simple method to determine the interaction between peptide and lipid bilayer and then deciding how to modify formulation from classic DepoFoam technology, multivesicular liposome of LXT-101 (DepoLXT-101) was prepared and characterized by in vitro evaluation. The electrostatic adsorption between peptide and lipid bilayer was observed by zeta potential and fluorescence spectrum. Anionic surfactants were added to stable the multiple emulsion and minimize the opposite effects resulted from drug. Encapsulation efficiency was determined by RP-HPLC. Morphology, particle size of DepoLXT-101 particles were characterized and their in vitro release was studied in sodium chloride solution. The DepoLXT-101 particles were prepared with good encapsulation efficiency, narrow size distribution and multivesicular construction. Over 95% of the DepoLXT-101 particles were in a size range of 5-20 microm. The in vitro assay in sodium chloride solution at 37 degrees C showed that 70%-90% of the peptide was released from particles slowly over 11 days. Multivesicular liposome sustained delivery of synthetic cationic peptides could be successfully prepared by the method.
Delayed-Action Preparations ; Drug Compounding ; Drug Delivery Systems ; methods ; Gonadotropin-Releasing Hormone ; antagonists & inhibitors ; Liposomes ; administration & dosage ; pharmacokinetics ; Oligopeptides ; administration & dosage ; pharmacokinetics ; Particle Size ; Technology, Pharmaceutical ; methods