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Background and Aims: Decompensated liver cirrhosis has a poor prognosis, with a median overall survival of two to four years, which is worse than for many oncological disorders. These patients are highly susceptible to infections due to increased systemic inflammation leading to kidney failure and death. The aim was to study the efficacy of albumin in reducing episodes of decompensation, preventing bacterial infection, kidney dysfunction and mortality., Method: Study involved patients with Child B or C cirrhosis with an albumin level below 3.0 g/dL, who were administered 20% human albumin weekly with standard medical treatment (SMT) for three months or till serum albumin levels were 4.0 g/dL (whichever is earlier) and compared with age and sex-matched controls who received only SMT. The primary end-point was six-month mortality and the secondary end-points were reduction in infections, kidney dysfunction, ascites recurrence, hepatic encephalopathy (HE), gastrointestinal (GI) bleed and complications of cirrhosis., Results: From September 2021 to January 2023, 88 cases and 86 controls were taken and followed up for six months. Overall, six-month survival was not statistically significant between groups (95.1% vs. 91.9%; p = 0·330). The incidence of recurrence of ascites (34.09% vs. 59.3%, p < 0.001), kidney dysfunction (6.8% vs. 24.4%, p < 0.001), HE (15.9% vs, 37.2%, p = 0.015), spontaneous bacterial peritonitis (SBP) (3.4% vs 17.4%, p = 0.002) and non-SBP infections (7.9% vs. 18.6%, p = 0.038) were significantly less in cases as compared with controls; however, GI bleed (14.8% vs. 17.4%, p = 0.632) was not statistically significant., Conclusion: Long-term human albumin acts as a disease-modifying treatment in patients with decompensated cirrhosis., (© 2024. Indian Society of Gastroenterology.)

Improvement of longevity is an eternal dream of human beings. The accumulation of protein damages is considered as a major cause of aging. Here, we report that the injection of exogenous recombinant mouse serum albumin (rMSA) reduced the total damages of serum albumin in C57BL/6N mice, with higher level of free-thiols, lower levels of carbonyls and advanced glycation end-products as well as homocysteines in rMSA-treated mice. The healthspan and lifespan of C57BL/6N mice were significantly improved by rMSA. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. Moreover, the median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The rMSA used in this study is young and almost undamaged. We define the concept "young and undamaged" to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no carbonylation, no advanced glycation end-product, and no homocysteinylation. Here, "young and undamaged" exogenous rMSA used in the present study is much younger and less damaged than the endogenous serum albumin purified from young mice at 1.5 months of age. We predict that undamaged proteins altogether can further improve the healthspan and lifespan of mice.

In this article, we will describe the properties of albumin and its biological functions, types of sources that can be used to produce albumin nanoparticles, methods of producing albumin nanoparticles, its therapeutic applications and the importance of albumin nanoparticles in the production of pharmaceutical formulations. In view of the increasing use of Abraxane and its approval for use in the treatment of several types of cancer and during the final stages of clinical trials for other cancers, to evaluate it and compare its effectiveness with conventional non formulations of chemotherapy Paclitaxel is paid. In this article, we will examine the role and importance of animal proteins in Nano medicine and the various benefits of these biomolecules for the preparation of drug delivery carriers and the characteristics of plant protein Nano carriers and protein Nano cages and their potentials in diagnosis and treatment. Finally, the advantages and disadvantages of protein nanoparticles are mentioned, as well as the methods of production of albumin nanoparticles, its therapeutic applications and the importance of albumin nanoparticles in the production of pharmaceutical formulations.

Background: Hemoglobin vesicles have been developed as artificial oxygen carriers, and they have the potential to serve as a substitute for red blood cell transfusion., Objective: This study aimed to evaluate the efficacy of hemoglobin vesicle infusion for the initial treatment instead of red blood cell transfusion in rabbits with massive obstetric hemorrhage., Study Design: Pregnant New Zealand white rabbits (28th day of pregnancy; normal gestation period, 29-35 days) underwent uncontrolled hemorrhage to induce shock by transecting the right midartery and concomitant vein in the myometrium. Subsequently, rabbits received isovolemic fluid resuscitation through the femoral vein with an equivalent volume of hemorrhage every 5 minutes. Resuscitative infusion regimens included 5% human serum albumin (n=6), stored washed red blood cells with plasma (vol/vol=1:1; n=5), and hemoglobin vesicle with 5% human serum albumin (vol/vol=4:1; n=5). A total of 60 minutes after the start of bleeding, rabbits underwent surgical hemostasis by ligation of the bleeding vessels and then were monitored for survival within 24 hours., Results: During fluid resuscitation, hemoglobin vesicle infusion and red blood cell transfusion maintained a mean arterial pressure of >50 mm Hg and a hemoglobin concentration of >9 g/dL and prevented the elevation of plasma lactate. In contrast, resuscitation with 5% human serum albumin alone could not prevent hemorrhagic shock as evidenced by a low mean arterial pressure (40 mm Hg), a low hemoglobin concentration (2 g/dL), and a marked elevation of plasma lactate. All animals in the red blood cell group and the hemoglobin vesicle group survived more than 8 hours, whereas all animals in the 5% human serum albumin group died within 8 hours., Conclusion: Hemoglobin vesicle infusion may be effective in the initial management of massive obstetric hemorrhage., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Extended half-life of factor IX (FIX) demonstrated clinical benefit and lower treatment burden than standard half-life FIX products in clinical trials. We analysed the impact in efficacy, pharmacokinetics (PKs) and costs of the switch from nonacog alfa (rFIX) to albutrepenonacog alfa (rFIX-FP) in the first patient with haemophilia B (HB) treated in Spain outside clinical trials. A 7-year-old boy presented with HB with poor venous access and repetition infections using rFIX, which was switched to rFIX-FP. Prophylaxis was adjusted by PKs using WAPPS-Hemo tailoring from 100 IU/kg/week of rFIX to 80 IU/kg/3 weeks of rFIX-FP. Comparing 6 months before, rFIX-FP reduced 68.5% FIX consumption/kg and 58.3% infusion frequency, but total costs/weight showed a slight increase. Ratio of half-life between rFIX and rFIX-FP was 3.4-3.7. This case report revealed that switch to rFIX-FP decreased frequency and FIX consumption, without adverse events and bleeds., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Adherence to prophylaxis regimens is essential for bleed prevention in haemophilia but remains a challenge due to the need for frequent infusions., Aim: To evaluate patient adherence to prophylaxis regimens with a long-acting recombinant factor IX (rIX-FP; IDELVION ® ) in clinical studies and real-world practice., Methods: In two phase 3 clinical studies, patients with haemophilia B (FIX ≤2%) recorded their dose, dosing frequency and rIX-FP consumption in an e-diary. Adherence to prescribed prophylaxis regimens was assessed in all patients and to prescribed dose in patients ≥12 years only. Additionally, adherence to rIX-FP prophylaxis regimens in real-world practice was captured., Results: In clinical studies, 94.9% (n = 56/59) of patients ≥12 years and 100% (n = 27) of paediatric patients received ≥80% of the expected number of infusions for their assigned prophylaxis schedule. Overall, mean adherence rate was 95.5% across all prophylaxis regimens in patients ≥12 years and 97.9% with a 7-day regimen in paediatric patients. In patients ≥12 years, 85.7% (n = 54/63) were dose adherent, defined as receiving within 10% of their prescribed dose ≥80% of the time. In real-world practice, adherence was observed in 100% (n = 14 and n = 15, respectively) of patients in two haemophilia treatment centres and 57.1% (n = 4/7) of patients in a third centre; non-adherence (n = 3/7) was linked to insurance-related and parental issues., Conclusion: In clinical studies, patients with haemophilia B had high adherence rates to rIX-FP prophylaxis regimens with a variety of dosing intervals, enabling them to achieve very low bleeding rates. High adherence may also be achievable in real-world practice., (© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Some physicians co-administer albumin with loop diuretics to overcome diuretic resistance in critically ill hypoalbuminemia patients, though previous studies have reported conflicting results on this matter., Objective: The effects of adding albumin to furosemide to enhance its efficacy in critically ill hypoalbuminemia patients are evaluated., Methods: This was a non-blinded randomized trial. 49 adult critically ill patients with hypoalbuminemia and generalized edema who received randomly furosemide and furosemide/albumin complex were enrolled. The patients' urine was collected at intervals of 2, 4, 6 and 8 h after initiation of the furosemide treatment, and the urine output and urinary excretion of furosemide and sodium were measured. The urinary excretion of furosemide was considered an indicator of drug efficacy., Results: The amount of sodium and furosemide excreted in urine showed no significant differences between the two groups; however, the mean of the urinary excretion of furosemide in the first 2 h after drug infusion was significantly higher (p = 0.03) in the furosemide/albumin group. No significant correlation between APACHE II scores and serum albumin levels and the urinary excretion of furosemide was seen., Conclusion: The results indicated that there is not statistically significant differences between groups with furosemide alone and combined with albumin in urinary furosemide excretion. It seems that adding albumin for furosemide pharmacotherapy regime is not recommended as an intervention to increase furosemide efficacy in critically ill hypoalbuminemia patients., Trial Registration: IRCT with the registration number IRCT201412132582N12 in 23 February 2015; https://en.irct.ir/trial/2356 Graphical abstract.

The cytokine platelet factor 4 (PF4) enhances differentiation and cell viability of different stem cells lines in vitro. This study investigated whether PF4 addition to customary pig embryo semi-defined culture media can improve their developmental outcome (Experiment 1) and ultimately replace the need for bovine serum albumin (BSA, Experiment 2). Experiment 1 added PF4 (100-1000 ng/mL, 0 = control) to NCSU-23 with 0.4 mg/mL BSA culturing 3430 presumptive zygotes. Experiment 2 added PF4 (100-1000 ng/mL, 0 = Control-PVA) to a BSA-free medium (NCSU-23 with 0.3 mg/mL PVA) culturing 3820 presumptive zygotes. Zygote culture in NCSU-23 with 0.4 mg/mL BSA was used as overall control. All groups of Experiment 1 displayed similar rates of day 2-cleavage (range: 65.0 ± 10.9 to 70.0 ± 5.8%); of day 7-blastocyst rates (range: 46.6 ± 10.0 to 56.4 ± 8.2%) and of total day 7-blastocyst efficiency (range: 32.3 ± 8.3 to 37.2 ± 7.3%). Addition of PF4 did not affect total cell numbers of day 7 blastocysts (range: 44.1 ± 23.2 to 50.5 ± 26.4). In Experiment 2, PF4 accelerated embryo development, increasing (P < 0.01) blastocyst yield compared to 0-PF4, and blastocyst formation by day 5 adding PF4 100-500 ng/mL (range: 29.9 ± 7.8 to 31.8 ± 5.5%; P < 0.05) compared with BSA-control (17.2 ± 8.2%) and PF4 1000 ng/mL (15.5 ± 7.9%); showing similar blastocyst rates (range: 42.0 ± 11.5 to 49.3 ± 10.0%), total efficiency (28.0 ± 8.2 to 32.3 ± 7.1%) total cell numbers (range: 42.6 ± 19.3 to 45.7 ± 23.9) as BSA-controls. In conclusion, although PF4 did not show additive improvement under usual semi-defined, BSA-supplemented embryo media, it successfully replaced BSA sustaining porcine blastocyst production in chemically defined conditions., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Burns that affect ≥20% of the total body surface area (TBSA) trigger a major inflammatory response in addition to capillary leakage and loss of serum proteins including albumin. Persistent hypoalbuminemia is therefore common in major burn patients. The purpose of this study was to determine whether human albumin solutions can benefit major burn patients with persistent hypoalbuminemia., Methods: We conducted a retrospective review of major burn patients with ≥20% of TBSA involved at Taipei Veterans General Hospital between January 2007 and December 2018. Thirty-eight patients were enrolled. Patient demographics, burn characteristics, fluid balance, laboratory results, and outcomes were recorded through chart review., Result: No significant differences were found in the baseline characteristics of patients who received <25 mg/kg/%TBSA/day of human albumin solutions and those who received more than this amount. Renal replacement therapy, duration of mechanical ventilation, length of stay in the burn unit, and in-hospital mortality rate were not statistically different between the two groups. The serum C-reactive protein/albumin ratio was associated with in-hospital mortality (p = 0.036)., Conclusion: The administration of large amounts of albumin supplements for the correction of prolonged hypoalbuminemia in major burn patients had no significant benefits on mortality.

Periodontal disease is a complex problem which often interrelates with several serious systemic diseases. However, the satisfactory clinical therapy has yet to be achieved. Herein, serum albumin microspheres containing minocycline and zinc oxide nanoparticals (ZnO NPs) were prepared and incorporated in a Carbopol 940 ® hydrogel. Compared with 2% minocycline ointment (Perio ® ), the hydrogel has shown obvious therapy effects and the ability of gingival tissue self-repairing. The serum albumin microspheres containing 0.06% of minocycline and 0.025% of ZnO NPs presented an average size of 139 ± 0.42 nm using electrophoretic light scattering (n = 3). Photomicrographs obtained by TEM showed homogeneous and spherical-shaped particles. The encapsulation efficiency was 99.99% for minocycline and the slow-release time was more than 72 h with pH-sensitive property. The in vitro skin adhesion experiment showed that the largest bioadhesive force is 0.35 N. Moreover, the hydrogel showed broad-spectrum antimicrobial and effective antibacterial ability when concentration of the ZnO NPs was over 0.2 µg/mL. The cell survival rates were more than 85% below 0.8 mg/L of ZnO NPs, which proved its low toxicity and high security.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease (PD) as it specifically damages the nigrostriatal dopaminergic pathway. Recent studies in mice have, however, provided evidence that MPTP also compromises the integrity of the brain's vasculature. Photobiomodulation (PBM), the irradiation of tissue with low-intensity red light, mitigates MPTP-induced loss of dopaminergic neurons in the midbrain, but whether PBM also mitigates MPTP-induced damage to the cerebrovasculature has not been investigated. This study aimed to characterize the time course of cerebrovascular disruption following MPTP exposure and to determine whether PBM can mitigate this disruption. Young adult male C57BL/6 mice were injected with 80 mg/kg MPTP or isotonic saline and perfused with fluorescein isothiocyanate FITC-labelled albumin at various time points post-injection. By 7 days post-injection, there was substantial and significant leakage of FITC-labelled albumin into both the substantia nigra pars compacta (SNc; p < 0.0001) and the caudate-putamen complex (CPu; p ≤ 0.0003); this leakage partly subsided by 14 days post-injection. Mice that were injected with MPTP and treated with daily transcranial PBM (670 nm, 50 mW/cm 2 , 3 min/day), commencing 24 hours after MPTP injection, showed significantly less leakage of FITC-labelled albumin in both the SNc ( p < 0.0001) and CPu ( p = 0.0003) than sham-treated MPTP mice, with levels of leakage that were not significantly different from saline-injected controls. In summary, this study confirms that MPTP damages the brain's vasculature, delineates the time course of leakage induced by MPTP out to 14 days post-injection, and provides the first direct evidence that PBM can mitigate this leakage. These findings provide new understanding of the use of the MPTP mouse model as an experimental tool and highlight the potential of PBM as a therapeutic tool for reducing vascular dysfunction in neurological conditions., Competing Interests: The authors declare no conflict of interest.

Successful treatment of age-related macular diseases requires an effective controlled drug release system with less invasive route of administration in the eye to reduce the burden of frequent intravitreal injections for patients. In this study, we developed an episcleral implantable device for sustained release of ranibizumab, and evaluated its efficacy on suppression of laser-induced choroidal neovascularization (CNV) in rats. We tested both biodegradable and non-biodegradable sheet-type devices consisting of crosslinked gelatin/chitosan (Gel/CS) and photopolymerized poly(ethyleneglycol) dimethacrylate that incorporated collagen microparticles (PEGDM/COL). In vitro release studies of FITC-labeled albumin showed a constant release from PEGDM/COL sheets compared to Gel/CS sheets. The Gel/CS sheets gradually biodegraded in the sclera during the 24-week implantation; however, the PEGDM/COL sheets did not degrade. FITC-albumin was detected in the retina during 18 weeks implantation in the PEGDM/COL sheet-treated group, and was detected in the Gel/CS sheet-treated group during 6 weeks implantation. CNV was suppressed 18 weeks after application of ranibizumab-loaded PEGDM/COL sheets compared to a placebo PEGDM/COL sheet-treated group, and to the intravitreal ranibizumab-injected group. In conclusion, the PEGDM/COL sheet device suppressed CNV via a transscleral administration route for 18 weeks, indicating that prolonged sustained ranibizumab release could reduce the burden of repeated intravitreal injections., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mast cells have functional plasticity affected by their tissue microenvironment, which greatly impacts their inflammatory responses. Because lactic acid (LA) is abundant in inflamed tissues and tumors, we investigated how it affects mast cell function. Using IgE-mediated activation as a model system, we found that LA suppressed inflammatory cytokine production and degranulation in mouse peritoneal mast cells, data that were confirmed with human skin mast cells. In mouse peritoneal mast cells, LA-mediated cytokine suppression was dependent on pH- and monocarboxylic transporter-1 expression. Additionally, LA reduced IgE-induced Syk, Btk, and ERK phosphorylation, key signals eliciting inflammation. In vivo, LA injection reduced IgE-mediated hypothermia in mice undergoing passive systemic anaphylaxis. Our data suggest that LA may serve as a feedback inhibitor that limits mast cell-mediated inflammation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Interferon (IFN)-γ plays an important role in antiviral, anti-proliferative, immunomodulatory and pro-inflammatory activities. However, the short therapeutic half-life of IFN-γ lessens its efficacy. Albumin fusion strategy is one of the most effective ways to improve the pharmacokinetic properties of cytokines. In this study, N- and C-terminal canine albumin fusions with canine IFN-γ were expressed in the baculovirus expression system. The fusion proteins stimulated Stat1 phosphorylation at levels similar to that of the recombinant IFN. The antiviral, anti-proliferative and promote apoptosis activity of CSA-IFN-γ was lower than IFN-γ-CSA and both were less than that of recombinant IFN-γ. In vivo pharmacokinetics demonstrated a significantly longer half-life for CSA-IFN-γ (21.73 h) than for IFN-γ-CSA (6.51 h) and canine reIFN-γ (2.22 h) in Wistar rats. CSA-IFN-γ was also more effective than IFN-γ-CSA and canine reIFN-γ at inhibiting growth of canine renal malignant histiocytosis in nude mice. Our results indicated that a canine serum albumin fusion at the N-terminus of IFN-γ prolongs its half-life and improves its in vivo antitumor activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Hydrogen sulfide (H 2 S) is an endogenous gaseous transmitter known to play an important role in biological functions. For the hepatic and intrahepatic targeting of H 2 S prodrug at the cellular level, we developed two types of sulfo-albumins, in which five sulfide groups (source of H 2 S) were covalently bound to succinylated (Suc) or galactosylated (Gal) bovine serum albumin (BSA). Sulfo-BSA-Suc and polyethylene glycol (PEG)-Sulfo-BSA-Gal, both released H 2 S in the 5 mM glutathione solution, but not in the plasma. Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal were taken up by RAW264.7 cells (mouse macrophage-like cells) and Hep G2 cells (human hepatocellular carcinoma cells), respectively, and H 2 S was released. These results indicate that Sulfo-BSA-Suc and PEG -Sulfo-BSA-Gal selectively released H 2 S intracellularly. In a biodistribution study, up to 80% of 111 In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal rapidly accumulated in the liver, 30 min after intravenous injection in mice. Furthermore, 111 In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal predominantly accumulated in liver nonparenchymal (endothelial cells and Kupffer cells) and parenchymal cells (hepatocytes), respectively. These findings suggest that targeted delivery of H 2 S prodrug to a specific type of liver cells was successfully achieved by bioconjugation.

Background: Early enteral nutrition (EEN) after surgery had been reported to decrease morbidity and mortality. However, no meta-analysis performed on nutrition status and recovery after surgery to Colorectal cancer (CRC)., Aim: We aimed to estimate effect of EEN for postoperative CRC., Methods: Electronic databases were searched for randomized controlled trials published prior to September 2017. Papers comparing EEN after surgery to traditional nutritional regimen in CRC patients were selected. The chosen articles should containe one or more of the following outcome measures: serum albumin, prealbumin, transferrin, time to first flatus and postoperative hospital stay., Results: 2307 cases from 26 studies were included. The analysis showed that EEN was more effective in increasing serum albumin and prealbumin, promoting the recovery of gastrointestinal function, and decreasing the time of postoperative hospital stay, especially for colon cancer., Conclusion: EEN can improve nutritional status and promote intestinal function recovery for patients undergoing CRC surgery.

Background:: The prognostic significance of serum albumin levels in patients with sepsis has previously been reported; however, these studies have not excluded the potential confounding effect of exogenous albumin administration. In this study, we investigate the predictive value of serum albumin for the prognosis of severe sepsis without the interference of exogenous albumin administration., Methods:: A prospective cohort study was conducted from April to November 2014 in the internal and surgical intensive care units of a tertiary care hospital. During the study period, due to a supply shortage, patients were not treated with human albumin. Serum albumin levels were measured, and laboratory and clinical data were collected at the onset of severe sepsis. Prognostic factors were analyzed using receiver operating characteristic curve and multivariate Cox proportional hazard regression analysis. Survival was assessed by Kaplan-Meier method., Results:: One hundred sixteen patients were included in the study. The overall 28-day mortality was 26.7%. The most common infection sources were lower respiratory tract, abdomen/pelvis, and bloodstream. Compared to patients who survived, those who died had lower serum albumin levels and higher Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Receiver operating characteristic curves demonstrate that albumin level is a strong predictor of 28-day mortality, and the optimal cutoff value maximizing sensitivity and specificity is 29.2 g/L. Through multivariate Cox regression analysis, low serum albumin levels (<29.2 g/L) and APACHE II scores are identified as independent risk factors for mortality. Patients with lower serum albumin levels more often had abdominal/pelvic sources of infection, acute kidney or liver injury, septic shock, and higher APACHE II and SOFA scores. The 28-day survival rate was lower for patients with serum albumin below 29.2 g/L than for patients with serum albumin at or above this level., Conclusion:: Having excluded potential confounding effect of exogenous albumin administration, low serum albumin levels are associated with an increased risk of death in patients with severe sepsis.

Paclitaxel (PTX) is used as a major antitumor agent for the treatment of recurrent and metastatic breast cancer. For the clinical application of PTX, it needs to be dissolved in an oil/detergent-based solvent due to its poor solubility in an aqueous medium. However, the formulation often causes undesirable complications including hypersensitivity reactions and limited tumor distribution, resulting in a lower dose-dependent antitumor effect. Herein, we introduce a facile and oil-free method to prepare albumin-based PTX nanoparticles for efficient systemic cancer therapy using a conjugate of human serum albumin (HSA) and poly(ethyleneglycol) (PEG). PTX were efficiently incorporated in the self-assembled HSA-PEG nanoparticles (HSA-PEG/PTX) using a simple film casting and re-hydration procedure without additional processes such as application of high pressure/shear or chemical crosslinking. The spherical HSA-PEG nanoparticle with a hydrodynamic diameter of ca. 280 nm mediates efficient cellular delivery, leading to comparable or even higher cytotoxicity in various breast cancer cells than that of the commercially available Abraxane ® . When systemically administered in a mouse xenograft model for human breast cancer, the HSA-PEG-based nanoparticle formulation exhibited an extended systemic circulation for more than 96 h and enhanced intratumoral accumulation, resulting in a remarkable anticancer effect and prolonged survival of the animals.

Nanoparticles targeting transporters of the blood-brain barrier (BBB) are promising candidates to increase the brain penetration of biopharmacons. Solute carriers (SLC) are expressed at high levels in brain endothelial cells and show a specific pattern at the BBB. The aim of our study was to test glutathione and ligands of SLC transporters as single or dual BBB targeting molecules for nanovesicles. High mRNA expression levels for hexose and neutral amino acid transporting SLCs were found in isolated rat brain microvessels and our rat primary cell based co-culture BBB model. Niosomes were derivatized with glutathione and SLC ligands glucopyranose and alanine. Serum albumin complexed with Evans blue (67 kDa), which has a very low BBB penetration, was selected as a cargo. The presence of targeting ligands on niosomes, especially dual labeling, increased the uptake of the cargo molecule in cultured brain endothelial cells. This cellular uptake was temperature dependent and could be decreased with a metabolic inhibitor and endocytosis blockers filipin and cytochalasin D. Making the negative surface charge of brain endothelial cells more positive with a cationic lipid or digesting the glycocalyx with neuraminidase elevated the uptake of the cargo after treatment with targeted nanocarriers. Treatment with niosomes increased plasma membrane fluidity, suggesting the fusion of nanovesicles with endothelial cell membranes. Targeting ligands elevated the permeability of the cargo across the BBB in the culture model and in mice, and dual-ligand decoration of niosomes was more effective than single ligand labeling. Our data indicate that dual labeling with ligands of multiple SLC transporters can potentially be exploited for BBB targeting of nanoparticles., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Purpose- A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms. Methods- Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells. Results- Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin. Conclusions- HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.

Metastasis is the leading cause of cancer-related deaths. A number of chemotherapeutic and early diagnosis strategies, including nanomedicine, have been developed to target metastatic tumor cells. However, simultaneous inhibition and imaging of metastasis is yet to be fully achieved. Methods: To overcome this limitation, we have developed human serum albumin-based nanoparticles (tHSA-NPs) with photoacoustic imaging capability, which target carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6). CEACAM6 is highly expressed in metastatic anoikis-resistant tumor cells. Results: In vitro , the CEACAM6-targeting tHSA-NPs efficiently targeted CEACAM6-overexpressing metastatic anoikis-resistant tumor cells. In vivo , CEACAM6-targeting tHSA-NPs administered intravenously to BALB/c nude mice efficiently inhibited lung metastasis in circulating anoikis-resistant tumor cells compared to the controls. In addition, anoikis-resistant tumor cells can be successfully detected by photoacoustic imaging, both in vitro and in vivo, using the intrinsic indocyanine green-binding affinity of albumin. Conclusion: In summary, the CEACAM6-targeting albumin-based nanoparticles allowed the delivery of drugs and photoacoustic imaging to metastatic anoikis-resistant tumor cells in vitro and in vivo . Based on the expression of CEACAM6 in a variety of tumors, CEACAM6-targeting nanomedicine might be used to target various types of metastatic tumor cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Intravitreal mobility of nanocarriers may have implications on the efficacy of the encapsulated drug in the treatment of vitreo-retinal diseases, with any changes in the integrity of the vitreous microstructure influencing nanoparticle biodistribution. This study investigated enzymatically digested vitreous models to mimic the aging eye. Collagenase, hyaluronidase, or trypsin was employed to selectively digest the structural components of the vitreous. Physical properties of digested bovine vitreous were initially assessed via texture analysis and oscillatory shear testing. Morphological changes in bovine vitreous microstructure were visualized by scanning electron microscopy and diffusion dynamics of hyaluronic acid coated nanoparticles through degraded porcine and bovine vitreous were examined using fluorescence spectroscopy and multiple particle tracking microscopy, respectively. After enzymatic treatment, the vitreous liquefied and its dynamic mechanical properties significantly changed with a decrease in stiffness and an increase in damping capacity. Micrographs confirmed specific digestion of each of the structural vitreous components. Furthermore, enzymatic degradation reduced steric hindrance and enhanced convective flow within the vitreous, resulting in increased intravitreal nanoparticle mobility which could alter the drug pharmacokinetics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A major feature of the injury sustained by the kidney during obstructive nephropathy is a profound induction of apoptosis in the tubular epithelium. In this study, we explored the central roles of mitochondria and the mechanism of the protective effect of the mitochondrial targeted peptides in tubular cell apoptosis and interstitial fibrosis during obstructive nephropathy. Unilateral ureter obstruction (UUO) was performed on rats, and the animals were randomly assigned to intravenous treatment with normal saline, rat serum albumin (RSA), or HOCl-rat serum albumin (HOCl-RSA) in the presence or absence of SS-31. A sham-operation control group was set up by left ureteral dissociation but not ligation. Compared with the control group, UUO animals displayed fibrotic abnormalities, accompanied by increased expression of collagen-I, fibronectin, α-SMA protein and mRNA in the renal interstitium. They also displayed oxidative stress, as evidenced by increased levels of HOCl-alb, TBARS, and mitochondrial reactive oxygen species (ROS) and a decrease in MnSOD activity in the renal homogenate. Damage to mitochondrial structure and functions was observed, as evidenced by a decrease in the mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and release of cytochrome C (cyto C) from the mitochondria to the cytoplasm. These changes were accompanied by activation of caspase-3, caspase-7, caspase-9, and PARP-1 and increased apoptotic cells in the proximal tubules. HOCl-RSA challenge further exacerbated the above biological effects in UUO animals, but these effects were prevented by administration of SS-31. These data suggested that accumulation of HOCl-alb may promote tubular cell apoptosis and interstitial fibrosis, probably related to mitochondrial oxidative stress and damage, and that SS-31 might contribute to apoptotic pathway suppression via scavenging of ROS in the mitochondria.

Background: shock refers to a physiological situation that puts life at risk. Its early identification and the timely institution of therapeutic measures can avoid death. Despite the frequent administration of fluid therapy as a treatment for shock, the type and dose of fluids to be delivered remain undetermined., Aim: to determine the type of fluids to be administered and the type of approach to be performed in the different types of shock., Method: integrative literature review., Results: data about fluid therapy in hypovolaemic and distributive shock were obtained, specifically in the haemorrhagic and the septic types. None of the articles addressed cardiogenic shock., Conclusion: hypotensive resuscitation, with blood, is the most appropriate approach in haemorrhagic shock. There remains a question regarding the best approach in septic shock. However, conservative fluid therapy seems to be appropriate, with preference given to the administration of balanced crystalloids or albumin as an alternative.

Hydrogels are highly attractive delivery vehicles for therapeutic proteins. Their innate biocompatibility, hydrophilicity and aqueous permeability allow stable encapsulation and release of proteins. The release rates also can be controlled simply by altering the crosslinking density of the polymeric network. However, the crosslinking density also influences the mechanical properties of hydrogels, generally opposite to the permeability. In addition, the release of larger proteins may be hindered below critically diminished porosity determined by the crosslinking density. Herein, the physical properties of the hydrogels are tuned by presenting functional pendant chains, independent of crosslinking density. Heterobifunctional poly(ethylene glycol) monomethacrylate (PEGMA) with various end functional groups is synthesized and copolymerized with PEG dimethacrylate (PEGDA) to engineer PEG hydrogels with pendant PEG chains. The pendant chains of the PEG hydrogels consisting of sulfonate, trimethylammonium chloride, and phenyl groups are utilized to provide negative charge, positive charge and hydrophobicity, respectively, to the hydrogels. The release rates of proteins with different isoelectric points are controlled in a wide range by the type and the density of functional pendant chains via electrostatic and hydrophobic interactions.

The green synthesis of nanoparticles has received increasing attention due to the growing demand to produce safe, cost-effective, and eco-friendly technology for nanomaterials synthesis. We report on the use of aqueous Croton bonplandianum (Family: Euphorbiaceae, Genus: Croton) leaves extract for the preparation of silver nanoparticles (AgNPs) without using any external reducing and stabilizing agent. Ultraviolet-visible spectroscopy showed maximum absorbance at 446 nm due to surface plasmon resonance of AgNPs. Energy dispersive X-ray spectra also supported the existence of AgNPs. An average diameter (d = ~17.4 nm) of the spherical AgNPs was determined from the transmission electron microscopic images. Hydrodynamic size (d = ~21.1 nm) was determined by dynamic light scattering. Fourier transform infrared analysis designed that the functional groups like O-H, N-H, [Formula: see text], CONH 2 , and COOH participated in the AgNPs formation. The negative zeta potential value (-19.3 mV) of the AgNPs indicated its dispersion and stability. The AgNPs exhibited strong antibacterial activity against Escherichia coli ATCC 25922 and 1.5 nM proved to be minimum inhibitory concentration for it. Hemolysis assay demonstrated the blood compatibility of the AgNPs toward human RBCs. The binding affinity of the AgNPs toward human hemoglobin and human serum albumin (HSA) was also determined by means of fluorescence spectroscopy. The circular dichroism spectroscopy revealed that the native structures of human hemoglobin and HSA remain unchanged, but its secondary structures were slightly changed upon interaction with AgNPs. Overall, it can be concluded that the AgNPs may be applied in the area of nanomedicines.

Liver fibrogenesis is associated with excessive production of extracellular matrix by myofibroblasts that often leads to cirrhosis and consequently liver dysfunction and death. Novel protein-based antifibrotic drugs show high specificity and efficacy, but their use in the treatment of fibrosis causes a high burden for patients, since repetitive and long-term parenteral administration is required as most proteins and peptides are rapidly cleared from the circulation. Therefore, we developed biodegradable polymeric microspheres for the sustained release of proteinaceous drugs. We encapsulated the drug carrier pPB-HSA, which specifically binds to the PDGFβR that is highly upregulated on activated myofibroblasts, into microspheres composed of hydrophilic multi-block copolymers composed of poly(l-lactide) and poly ethylene glycol/poly(ϵ-caprolactone), allowing diffusion-controlled release. Firstly, we estimated in mice with acute fibrogenesis induced by a single CCl4 injection the half-life of I125-labeled pPB-HSA at 40 min and confirmed the preferential accumulation in fibrotic tissue. Subsequently, we determined in the Mdr2 −/− mouse model of advanced biliary liver fibrosis how the subcutaneously injected microspheres released pPB-HSA into both plasma and fibrotic liver at 24 h after injection, which was maintained for six days. Although the microspheres still contained protein at day seven, pPB-HSA plasma and liver concentrations were decreased. This reduction was associated with an antibody response against the human albumin-based carrier protein, which was prevented by using a mouse albumin-based equivalent (pPB-MSA). In conclusion, this study shows that our polymeric microspheres are suitable as sustained release formulation for targeted protein constructs such as pPB-HSA. These formulations could be applied for the long-term treatment of chronic diseases such as liver fibrosis.

Purpose: Alveolar clearance of proteins, such as albumin, plays an essential role in recovery from lung injuries. Albumin is known to be oxidized by reactive oxygen species (ROS), leading to generation of advanced oxidation protein products (AOPP)-albumin in the alveolar lining fluid. In this study, we aimed to characterize the uptake of FITC-labeled AOPP-albumin (FITC-AOPP-albumin) into human alveolar epithelial cell line, A549., Methods: FITC-AOPP-albumin uptake into A549 cells and its effect of ROS generation was evaluated using fluorescence spectrometer and flow cytometry, respectively., Results: FITC-AOPP-albumin was taken up by A549 cells in a time- and temperature-dependent fashion, and showed saturation kinetics with a Km value of 0.37 mg/mL. The uptake of FITC-AOPP-albumin was suppressed by phenylarsine oxide, a clathrin-mediated endocytosis inhibitor, but not by indomethacin and nystatin, caveolae-mediated endocytosis inhibitors, or 5-(N-ethyl-N-isopropyl) amiloride, a macropinocytosis inhibitor. AOPP-albumin induced ROS generation in A549 cells, suggesting that alveolar clearance of AOPP-albumin should be important to prevent further ROS generation., Conclusion: AOPP-albumin is transported into alveolar epithelial cells through clathrin-mediated endocytosis, which may be important to prevent further ROS generation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

The construction of Fab phage libraries requires the cloning of domains from both the light and the heavy chain of antibodies. Despite the advent of powerful strategies such as splicing-by-overlap extension PCR, obtaining high quality libraries with excellent coverage remains challenging. Here, we explored the use of type IIS restriction enzymes for the seamless cloning of Fab libraries. We analyzed human, murine and rabbit germline antibody repertoires and identified combinations of restriction enzymes that exhibit very few or no recognition sites in the antibody sequences. We describe three phagemid vectors, pUP-22Hb, pUP-22Mc and pUP-22Rc, which were employed for cloning the Fab repertoire of these hosts using BsmBI and SapI (human) or SapI alone (mouse and rabbit). Using human serum albumin as a model immunization, we built a mouse/human chimeric Fab library and a mouse Fab library in a single step ligation and successfully panned multiple cognate antibodies. The overall process is highly scalable and faster than PCR-based techniques, with a Fab insertion success rate of around 80%. By using carefully chosen overhangs on each end of the antibody domains, this approach paves the way to the universal, sequence- and vector-independent cloning and reformatting of antibody libraries., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Liposomes possess good biocompatibility and excellent tumor-targeting capacity. However, the rapid premature release of lipophilic drugs from the lipid bilayer of liposomes has negative effect on the tumor-targeted drug delivery of liposomes. In this study, a lipophilic antitumor drug-chlorambucil (CHL)-was encapsulated into the aqueous interior of liposomes with the aid of albumin to obtain the CHL-loaded liposomes/albumin hybrid nanoparticles (CHL-Hybrids). The in vitro accumulative release rate of CHL from CHL-Hybrids was less than 50% within 48 h, while the accumulative CHL release was more than 80% for CHL-loaded liposomes (CHL-Lip). After intravenous injection into rats, the half-life (t 1/2β  = 5.68 h) and maximum blood concentration (C max  = 4.58 μg/mL) of CHL-Hybrids were respectively 1.1 times and 3.5 times higher than that of CHL-Lip. In addition, CHL-Hybrids had better tumor-targeting capacity for it significantly increased the drug accumulation in B16F10 tumors, which contributed to the significantly control of tumor growth compared with CHL-Lip. Furthermore, CHL-Hybrid-treated B16F10 melanoma-bearing mice displayed the longest median survival time of 30.0 days among all the treated groups. Our results illustrated that the proposed hybrids drug delivery system would be a promising strategy to maintain the controlled release of lipophilic antitumor drugs from liposomes and simultaneously facilitate the tumor-targeted drug delivery.

Albumin has a number of important physiologic functions, which include maintaining oncotic pressure, transporting various agents (fatty acids, bile acids, cholesterol, metal ions, and drugs), scavenging free oxygen radicals, acting as an antioxidant, and exerting an antiplatelet effect. Hypoalbuminemia in adults, defined by an intravascular albumin level of <3.5 g/dL, is associated with poor postoperative outcomes in patients undergoing surgical intervention. Although the relationship of hypoalbuminemia and poor surgical outcome has been known for many years, the pathophysiology behind the relationship is unclear. Three theoretical constructs might explain this relationship. First, albumin might serve as a nutritional marker, such that hypoalbuminemia represents poor nutritional status in patients who go on to experience poor postoperative outcomes. Second, albumin has its own pharmacologic characteristics as an antioxidant or transporter, and therefore, the lack of albumin might result in a deficiency of those functions, resulting in poor postoperative outcomes. Or third, albumin is known to be a negative acute phase protein, and as such hypoalbuminemia might represent an increased inflammatory status of the patient, potentially leading to poor outcomes. A thorough review of the literature reveals the fallacy of these arguments and fails to show a direct cause and effect between low albumin levels per se and adverse outcomes. Interventions designed solely to correct preoperative hypoalbuminemia, in particular intravenous albumin infusion, do little to change the patient's course of hospitalization. While surgeons may use albumin levels on admission for their prognostic value, they should avoid therapeutic strategies whose main endpoint is correction of this abnormality.

The abnormal tumor microenvironment (TME) featured with hypoxia, acidosis, dense extracellular matrix and increased tumor interstitial fluid pressure is closely related with the resistance of tumors to various therapies. Herein, a unique type of biocompatible nanoscale delivery system is fabricated by utilizing a chemotherapeutic drug, paclitaxel (PTX), to induce co-assembly of catalase and human serum albumin (HSA), the latter of which is pre-modified with chlorine e6 (Ce6), forming smart multifunctional HSA-Ce6-Cat-PTX nanoparticles via a rather simple one-step method. Upon intravenous injection, HSA-Ce6-Cat-PTX nanoparticles show high tumor accumulation and efficient intra-tumoral diffusion, likely owning to their changeable sizes that can maintain large initial sizes (~100nm) during blood circulation and transform into small protein-drug complexes (<20nm) within the tumor. Meanwhile, catalase within those nanoparticles could trigger decomposition of endogenic TME H 2 O 2 to generate oxygen in-situ so as to relieve tumor hypoxia. This effect together with PTX-induced intra-tumoral perfusion enhancement is able to dramatically modulate TME to favor the anti-tumor effect in the combined photodynamic/chemotherapy with HSA-Ce6-Cat-PTX. Thus, our work presents a simple drug-induced self-assembly strategy to fabricate enzyme-loaded therapeutic albumin nanoparticles for synergistic cancer combination therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Nanoparticles are used to deliver anticancer drugs to solid tumors. However, clinical development of nanoparticles is challenging because of their limitations in physicochemical properties, such as low drug loading efficiency and poor circulation stability. Low drug loading not only causes technical difficulty in administration but also increases the amount of co-delivered carrier materials, imposing biological burdens to patients. Poor circulation stability causes loss of pharmacokinetics benefits of nanoparticles. To overcome these challenges, we developed an albumin-coated nanocrystal (NC) formulation of paclitaxel (PTX) with 90% drug loading and high serum stability. The NC was produced by inducing crystallization of PTX in aqueous medium, coating the surface with albumin, and removing extra non-drug ingredients. Among three types of NC produced with different crystallization conditions, NC crystallized in the medium containing Pluronic F-127 then coated with albumin ("Cim-F-alb") had the smallest size and the most native albumin, thus showing the most favorable cell interaction profiles (low uptake by J774A.1 macrophages and high uptake by SPARC + B16F10 melanoma cells). Cim-F-alb remained more stable in undiluted serum than Abraxane, a commercial albumin-based PTX nanoparticle formulation, while maintaining comparable cytotoxicity to those of Abraxane and solvent-dissolved PTX. In a mouse model of B16F10 melanoma, Cim-F-alb showed higher antitumor efficacy than Abraxane at the same dose. This study demonstrates the feasibility and benefits of delivering an anticancer drug using a carrier-free nanoparticle formulation with good circulation stability., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Research about antibody specificity spectra was conducted to develop single-specific antibodies or broad-specific antibodies. Aflatoxins, as one class of high-toxicity mycotoxins, were selected as the research targets to investigate the effect of the immunogen dose on antibody specificity spectra. For this aim, 16 monoclonal antibodies were induced by low or high doses of aflatoxin B₁-BSA, and 34 monoclonal antibodies were induced by low or high doses of aflatoxin M₁-BSA. The specificities of the antibodies induced, whether by aflatoxin B₁ conjugate or aflatoxin M₁ conjugate, indicated that the low dose of the immunogen induced a narrow spectrum of antibody specificity, while the high dose of the immunogen showed an advantage to form a broad spectrum of antibody specificity. Therefore, this report provides important information for the development of new antibodies against small molecules like aflatoxins., Competing Interests: The authors declare no conflict of interest.

Rationale: The transport of interstitial fluid and solutes into lymphatic vessels is important for maintaining interstitial homeostasis and delivering antigens and soluble factors to the lymph node for immune surveillance. Transendothelial transport across lymphatic endothelial cells (LECs) is commonly considered to occur paracellularly, or between cell-cell junctions, and driven by local pressure and concentration gradients. However, emerging evidence suggests that LECs also play active roles in regulating interstitial solute balance and can scavenge and store antigens, raising the possibility that vesicular or transcellular pathways may be important in lymphatic solute transport., Objective: The aim of this study was to determine the relative importance of transcellular (vesicular) versus paracellular transport pathways by LECs and how mechanical stress (ie, fluid flow conditioning) alters either pathway., Methods and Results: We demonstrate that transcellular transport mechanisms substantially contribute to lymphatic solute transport and that solute uptake occurs in both caveolae- and clathrin-coated vesicles. In vivo, intracelluar uptake of fluorescently labeled albumin after intradermal injection by LECs was similar to that of dermal dendritic cells. In vitro, we developed a method to differentially quantify intracellular solute uptake versus transendothelial transport by LECs. LECs preconditioned to 1 µm/s transmural flow demonstrated increased uptake and basal-to-apical solute transport, which could be substantially reversed by blocking dynamin-dependent vesicle formation., Conclusions: These findings reveal the importance of intracellular transport in steady-state lymph formation and suggest that LECs use transcellular mechanisms in parallel to the well-described paracellular route to modulate solute transport from the interstitium according to biomechanical cues., (© 2017 American Heart Association, Inc.)

Background: Plasma expansion in acute ischemic stroke has potential to improve cerebral perfusion, but the long-term effects on functional outcome are mixed in prior trials. The goal of this study was to evaluate how the magnitude of plasma expansion affects neurological recovery in acute stroke., Methods: This was a secondary analysis of data from the Albumin in Acute Stroke Part 2 trial investigating the relationship between the magnitude of overall intravenous volume infusion (crystalloid and colloid) to clinical outcome. The data were inclusive of 841 patients with a mean age of 64 years and a median National Institutes of Health Stroke Scale (NIHSS) of 11. In a multivariable-adjusted logistic regression model, this analysis tested the volume of plasma expansion over the first 48 h of hospitalization as a predictor of favorable outcome, defined as either a modified Rankin Scale score of 0 or 1 or a NIHSS score of 0 or 1 at 90 days. This model included all study patients, irrespective of albumin or isotonic saline treatment., Results: Patients that received higher volumes of plasma expansion more frequently had large vessel ischemic stroke and higher NIHSS scores. The multivariable-adjusted model revealed that there was decreased odds of a favorable outcome for every 250 ml additional volume plasma expansion over the first 48 h (OR 0.91, 95 % CI, 0.88-0.94)., Conclusions: The present study demonstrates an association between greater volume of plasma expansion and worse neurological recovery.

Purpose: The ocular half-life of intravitreally (IVT) injected drugs is of major relevance for the suitability of a drug intended for chronic intraocular treatment, as the half-life determines the dosing frequency. Thus, half-life extension principles are very attractive as they can reduce the IVT dosing frequency. In this study, we investigated the ocular pharmacokinetics (PK) of the IVT injected Nanobody ® BI-X and whether the noncovalent binding of BI-X to vitreous albumin could increase its ocular half-life., Methods: Wistar rats were dosed IVT with 3 μg BI-X alone or coadministered with human serum albumin (HSA), and the ocular exposure was measured in a pilot experiment using whole eye homogenates. New Zealand White rabbits received IVT injections of 500 μg BI-X alone or coadministration with HSA. Concentrations of BI-X were determined in aqueous humor, vitreous body and plasma and pharmacokinetic parameters were calculated., Results: Ocular concentrations of BI-X in rats were about 10- or 3-fold higher at 24 and 72 h, respectively, when dosed with HSA. In rabbits, coadministration with albumin led to an about 3-fold increased vitreous half-life and an about 5-fold higher exposure in vitreous humor., Conclusion: As small amounts of albumin are present in the vitreous body of healthy human eyes and the albumin concentration is even increased under disease conditions like diabetic retinopathy, high affinity binding to albumin may be a promising strategy to extend the half-life of IVT injected drugs, allowing for longer dosing intervals.

Congenital analbuminaemia is a rare autosomal recessive disorder that is characterised by a severe reduction or total absence of serum albumin. This condition has implications for therapeutics as a large proportion of commonly used drugs are plasma protein bound where albumin is the primary component of plasma protein. This is the first case report of pregnancy in a patient with congenital analbuminaemia in the medical literature. In the absence of drug dosage guidelines for patients with congenital analbuminaemia, a list of drugs which may be required for this patient during pregnancy, delivery and/or emergency situations were compiled by a multidisciplinary team. Our patient suffered from polyhydramnios during her pregnancy which was successfully managed with albumin transfusions and had a normal vaginal delivery with no complications in the intrapartum or postpartum period. The management and unique challenges of pregnancy in a patient with congenital analbuminaemia are discussed., Competing Interests: Competing interests: None declared., (2017 BMJ Publishing Group Ltd.)

The delivery of most therapeutic agents is rendered ineffective for the treatment of brain diseases due to the presence of the blood-brain barrier (BBB). The goal of this study was to investigate the effect of pre-infusion focused ultrasound (FUS) and microbubbles on the distribution of direct brain infusion in vivo. A single-element FUS transducer was used in all sonications, which were carried out immediately prior to direct infusion procedures. Mice received direct infusion of either Gadolinium-labeled albumin (Gd-albumin, 74 kDa) or adeno-associated virus (AAV, ∼4 MDa). The volumes of Gd-albumin at 30 min were deemed comparable ( P = 0.334) between the direct infusion (DI)-only group and the FUS + DI group. At 120 min, the FUS + DI group showed significantly higher contrast-enhanced volume (9.76 ± 0.74 mm 3 ) than the DI-only group (7.14 ± 0.34 mm 3 ). For mice infused with AAV, the total volume of transduction was estimated as GFP-positive regions and FUS + DI group demonstrated significantly higher ( P = 0.017) transduction efficiency in vivo. In conclusion, enhanced bio-distribution of directly infused agents was observed when the targeted region was pre-conditioned with FUS and microbubbles. Focused ultrasound has the potential, as an adjuvant technique, to significantly enhance direct brain infusion and achieve the desired therapeutic outcomes.

Purpose: To investigate the impacts of albumin synergized with hydroxyethyl starch (HES) on early microvascular albumin leakage after major abdominal surgery in rabbits., Methods: Forty male Japanese rabbits were randomly divided into four groups: the control group, the saline group, the albumin group, and the Syn group (hydroxyethyl starch+albumin). The latter three groups were performed gastrectomy plus resection of pancreatic body and tail and splenectomy. The serum albumin concentration was detected before and 48h after surgery, and the conditions of mesenteric microvascular leakage in these 4 groups were observed under microscope 48 h after surgery to calculate the leakage rate., Results: Compared with the saline group, the albumin group and the Syn group exhibited significantly increased serum albumin concentrations 48h after surgery (P<0.05). The albumin leakage rate was the most obvious in the albumin group, followed by the saline group, while that in the Syn group was the minimal, and there existed significant differences among these groups (P<0.05) ., Conclusion: Simple administration of albumin in the early stage after major abdominal surgery could increase the albumin leakage, while the synergization of albumin and hydroxyethyl starch could reduce the albumin leakage.

Development of biocompatible/biodegradable materials with multiple functionalities via simple methods for cancer combination therapy has attracted great attention in recent years. Herein, paclitaxel (PTX), a popular anti-tumor chemotherapeutic drug, is used to induce the self-assembly of human serum albumin (HSA) pre-labeled with radionuclide I-131, obtaining 131 I-HSA-PTX nanoparticles for combined chemotherapy and radioisotope therapy (RIT) of cancer. Such 131 I-HSA-PTX nanoparticles show prolonged blood circulation time, high tumor specific uptake and excellent intra-tumor penetration ability. Interestingly, as revealed by in vivo photoacoustic imaging and ex vivo immunofluorescence staining, PTX delivered into the tumor by HSA-nanoparticle transportation can remarkably enhance the tumor local oxygen level and suppress the expression of HIF-1α, leading to greatly relieved tumor hypoxia. As the results, the combined in vivo chemotherapy & RIT with 131 I-HSA-PTX nanoparticles in the animal tumor model offers excellent synergistic therapeutic efficacy, likely owing to the greatly modulated tumor microenvironment associated with PTX-based chemotherapy. Therefore, in this work, a simple yet effective therapeutic agent is developed for synergistic chemo-RIT of cancer, promising for future clinic translations in cancer treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Due to their small size and unique properties, multifunctional nanoparticles arise as versatile delivery systems easily grafted with a vast array of functional moieties, such as anticancer cytotoxic chemotherapeutics and targeting agents. Here, we formulated a multifunctional gold-nanoparticle (AuNP) system composed of a monoclonal antibody against epidermal growth factor receptor (EGFR) (anti-EGFR D-11) for active targeting and a Co(II) coordination compound [CoCl(H 2 O)(phendione) 2 ][BF 4 ] (phendione=1,10-phenanthroline-5,6-dione) (TS265) with proven antiproliferative activity towards cancer cells (designated as TargetNanoTS265). The efficacy of this nanoformulation, and the non-targeted counterpart (NanoTS265), were evaluated in vitro using cancer cell models and in vivo using mice xenografts. Compared to the free compound, both nanoformulations (TargetNanoTS265 and NanoTS265) efficiently delivered the cytotoxic cargo in a controlled selective manner due to the active targeting, boosting tumor cytotoxicity. Treatment of HCT116-derived xenografts tumors with TargetNanoTS265 led to 93% tumor reduction. This simple conceptual nanoformulation demonstrates the potential of nanovectorization of chemotherapeutics via simple assembly onto AuNPs of BSA/HAS-drug conjugates that may easily be expanded to suit other cargo of novel compounds that require optimized controlled delivery to cancer target., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The diagnosis of myocarditis traditionally relies on invasive endomyocardial biopsy but none of the imaging studies so far are specific for infiltration of the inflammatory cells itself. We synthesized 68 Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA) by conjugating human serum albumin with mannose, followed by conjugation with NOTA and labeling it with 68 Ga. The efficacy of 68 Ga-NOTA-MSA positron emission tomography (PET) for imaging myocardial inflammation was tested in a rat myocarditis model. A significant number of mannose receptor-positive inflammatory cells infiltrated the myocardium in both human and rat myocarditis tissue. 68 Ga-NOTA-MSA uptake was upregulated in organs of macrophage accumulation, such as liver, spleen, bone marrow and myocardium (0.32 (0.31~0.33) for normal versus 1.02 (0.86~1.06) for myocarditis (median (range), SUV); n=4~6 per group, p-value=0.01). 68 Ga-NOTA-MSA uptake in the left ventricle was upregulated in myocarditis compared with normal rats (2.29 (1.42~3.40) for normal versus 4.18 (3.43~6.15) for myocarditis (median (range), average standard uptake value ratio against paraspinal muscle); n=6 per group, p-value<0.01), which was downregulated in rats with cyclosporine-A treated myocarditis (3.69 (2.59~3.86) for myocarditis versus 2.28 (1.76~2.60) for cyclosporine-A treated myocarditis; n=6 per group, p-value<0.01). The specificity of the tracer was verified by administration of excess non-labeled MSA. 68 Ga-NOTA-MSA uptake was significantly enhanced earlier in the evolution of myocarditis before any signs of inflammation could be seen on echocardiography. These results demonstrate the potential utility of visualizing infiltration of mannose receptor-positive macrophages with 68 Ga-NOTA-MSA PET in the early diagnosis of as well as in the monitoring of treatment response of myocarditis., Competing Interests: The authors have declared that no competing interest exists.

Albumin polymeric Nanoparticles (NPs) have opened a great expectancy as for controlled drug delivery due to their therapeutic potency. Concomitantly biodegradable NPs technologies with target linked structures to pave the way of personalised medicine are becoming increasingly important in sight of a therapeutically effective research technology. This is particularly attractive for nanoparticle-based cancer delivery systems, based on the known limitations and efforts to overcome. This new group of gamma irradiated-NPs inherited both the protein delivery properties and robustness of polymer forming structures, and gamma irradiation techniques that leave clean, innocuous and biodegradable NPs. These protein NPs made of serum albumin are referred to SA NPs that possesses several characteristics making them especially attractive to be considered as a drug delivery system. This review focused on methodologies actually being used in the synthesis and characterisation of albumin NPs and different author's opinions on strategic ways to treat cancerous cell-lines with NPs. Utterly, challenges being overthrown by researchers are brought up to anneal an effective, all in one targeted albumin NPs to passed through in vitro and preclinical trials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Sleep is a natural part of every individual's life. Delta sleep-inducing peptide (DSIP) is a nonapeptide that could promote sleep through the induction of slow wave sleep. However, little is known about the pharmacological effect of DSIP on insomnia., Objectives: The main objective of this study was to analyze the pharmacological effect of DSIP on insomnia., Methods: We designed a fusion protein containing N-terminal TAT-based transduction domain followed by human serum albumin and DSIP and designated this protein as PHD fusion protein. The PHD fusion protein were expressed in Pichia pastoris and purified. Mice were administered single subcutaneous injections three concentrations of PHD fusion protein (0.5, 1, 2 mg/kg), and the pharmacological activity of PHD fusion protein was studied using classic pentobarbitalinduced sleep test., Results: We expressed the PHD fusion protein in P. pastoris; furthermore, the PHD fused protein was purified to near homogeneity by DEAE Sepharose FF, Phenyl Sepharose HP and Blue Sepharose 6 FF. Our result showed that the increase of pentobarbital-induced hypnotic effect characterized by reducing sleep latency and prolonged sleep duration was observed for increasing concentrations of PHD fusion protein (P<0.05); moreover, different dose of PHD fusion protein could induce the mice to re-sleep in a dose-dependent manner, whereas higher doses of PHD fusion protein (1.0, 2.0 mg/kg) significantly increased the rate of sleep re-onset compared with the vehicle group of mice (P<0.05)., Conclusion: PHD fusion protein increased the hypnotic effects of pentobarbital by reducing sleep latency and prolonged sleep duration. The present study suggested PHD fusion protein could be a new drug candidate for insomnia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Biomacromolecules (>40 kDa) have been developed as drug delivery system (DDS) carriers of low-molecular weight drugs to promote these drugs' uptake by cancer tissues via enhanced permeability and retention (EPR) effects. Human serum albumin (HSA) has been found to accumulate in cancer tissues via this EPR effect. HSA is the most abundant protein in serum, which performs essential physiological functions such as the transportation of many endogenous and exogenous ligands. Nitric oxide (NO) is a very small ligand of HSA; it is a unique and diffusible molecular messenger that plays a central role in mammalian physiology. Although the in vivo half-life of NO is extremely short, HSA could prolong the half-life of NO via S-nitrosation at the position of Cys-34. S-Nitrosated HSA (mono-SNO-HSA) is called an 'Endogenous NO traffic protein,' due to the highly stable S-nitroso form in circulating blood, and to the efficiency of S-transnitrosation in cells that require NO. Mono-SNO-HSA possesses a very strong cytoprotective action via the induction of heme oxygenase-1. On the other hand, HSA reinforced with approximately seven NO molecules (poly-SNO-HSA), which we developed by means of chemical modification, possesses multiple anticancer activities. Our previous data clarified that the high expression of protein disulfide isomerase on the surface of cancer cells plays a very important role in the anticancer action of poly-SNO-HSA. In this review, we focus on the advantage of poly-SNO-HSA in treating intractable cancers from the viewpoint of drug delivery systems and drug resistance.

Chitosan-coated human serum albumin nanoparticles were functionalized by MUC1 aptamer to obtain a selective drug carrier toward cancers overexpressing MUC1. The negative charges of albumin nanoparticles were shifted to positive charges by surface modification with chitosan, and MUC1 was conjugated through an acrylate spacer. The cytotoxicity of targeted nanoparticles was significantly more than non-aptamer nanoparticles, and also the chitosan-coated nanoparticles had more cytotoxic effects than the negatively charged albumin nanoparticles. The IC 50 of targeted nanoparticles was 28 and 26% of free paclitaxel in MCF7 and T47D cells at 48h, respectively. Confocal laser scanning electron microscopy showed that aptamer conjugation and positive charge increase the cellular uptake. 66% of paclitaxel was released within 32h, but 100% of drug was released at pH=5.5 (similar cancer cells). The paclitaxel plasma amount was at a good level of 17.6% at 2h for increasing the chance of cellular uptake., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: A biodegradable polymeric sealant has been previously shown to reduce postoperative air leaks after open pulmonary resection. The aim of this study was to evaluate safety and efficacy during minimally invasive pulmonary resection., Methods: In a multicenter prospective single-arm trial, 112 patients with a median age of 69 years (range 34-87 years) were treated with sealant for at least one intraoperative air leak after standard methods of repair (sutures, staples or cautery) following minimally invasive pulmonary resection (Video-Assisted Thoracic Surgery (VATS) or Robotic-Assisted). Patients were followed in hospital and 1 month after surgery for procedure-related and device-related complications and presence of air leak., Results: Forty patients had VATS and 72 patients had Robotic-Assisted procedures with the majority (80/112, 71%) undergoing anatomic resection (61 lobectomy, 13 segmentectomy, 6 bilobectomy). There were no device-related adverse events. The overall morbidity rate was 41% (46/112), with major complications occurring in 16.1% (18/112). In-hospital mortality and 30-day mortality were 1.9% (2/103). The majority of intraoperative air leaks (107/133, 81%) were sealed after sealant application, and an additional 16% (21/133) were considered reduced. Forty-nine percent of patients (55/112) were free of air leak throughout the entire postoperative study period. Median chest tube duration was 2 days (range 1 - 46 days), and median length of hospitalization was 3 days (range 1 - 20 days)., Conclusions: This study demonstrated that use of a biodegradable polymer for closure of intraoperative air leaks as an adjunct to standard methods is safe and effective following minimally invasive pulmonary resection., Trial Registration: ClinicalTrials.gov: NCT01867658 . Registered 3 May 2013.

Aims: Advanced glycated albumin (AGE-albumin) adversely impairs macrophage lipid homeostasis in vitro, which may be prevented by angiotensin receptor blockers. In vivo studies are inconclusive whether AGE-albumin itself plays important role in early-stage atherogenesis. We aimed at investigating how AGE-albumin by itself drives atherosclerosis development in dyslipidemic non-diabetic mice and if its effects are due to the activation of renin-angiotensin system in the arterial wall and the expression of genes and proteins involved in lipid flux., Methods and Results: Murine albumin glycation was induced by incubation with 10mM glycolaldehyde and C-albumin with PBS alone. Twelve-week-old-male apoE knockout mice were submitted to a daily IP injection of control (C) or AGE-albumin (2mg/mL) during 30days with or without losartan (LOS: 100mg/L; C+LOS and AGE+LOS). Aortic arch was removed, and gene expression was determined by RT-PCR and protein content by immunofluorescence. Plasma lipid and glucose levels were similar among groups. Systolic blood pressure was similarly reduced in both groups treated with LOS. In comparison to C-albumin, aortic lipid infiltration was 5.3 times increased by AGE-albumin, which was avoided by LOS. LOS prevented the enhancement induced by AGE-albumin in Ager, Tnf and Cybb mRNA levels but did not reduce Olr1. Nfkb and Agt mRNA levels were unchanged by AGE-albumin. LOS similarly reduced Agtr1a mRNA level in both C and AGE-albumin groups. In AGE-albumin-treated mice, immunofluorescence for carboxymethyl-lysine, 4-hydroxynonenal and RAGE was respectively, 4.8, 2.6 and 1.7 times enhanced in comparison to C-albumin. These increases were all avoided by LOS., Conclusions: AGE-albumin evokes a pre-stage of atherogenesis in dyslipidemic mice independently of the presence of diabetes mellitus or modulation in the RAS in part by the induction of lipid peroxidation and inflammation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and aims. Steroid-related hepatotoxicity has become one of the most relevant causes of drug induced liver cholestasis. Some patients do not improve after standard medical treatment (SMT) and may therefore require other approaches, like extracorporeal liver support., Material and Methods: We report four cases of patients with pruritus, abnormal liver function tests and biopsy-proven anabolic steroid-induced cholestasis who were unresponsive to SMT. They underwent treatment with albumin dialysis (Molecular Adsorbent Recirculating System -MARS®-). A minimum of two MARS sessions were performed., Results: After MARS® procedure, patients' symptoms improved, as well as liver function tests, thus avoiding liver transplantation., Conclusion: Albumin dialysis appears as a valuable therapeutic option for the management of anabolic steroid-induced cholestasis in patients that are unresponsive to SMT.