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The formulation, physicochemical stability and bioaccessibility of astaxanthin (AST) loaded oil-in-water nanoemulsions fabricated using gypenosides (GPs) as natural emulsifiers was investigated and compared with a synthetic emulsifier (Tween 20) that is commonly applied in food industry. GPs were capable of producing nanoemulsions with a small volume mean diameter ( d 4,3  = 125 ± 2 nm), which was similar to those prepared using Tween 20 ( d 4,3  = 145 ± 6 nm) under the same high-pressure homogenization conditions. GPs-stabilized nanoemulsions were stable against droplet growth over a range of pH (6–8) and thermal treatments (60–120 °C). Conversely, instability occurred under acidic (pH 3–5) and high ionic strength (25–100 mM CaCl 2 ) conditions. In comparison with Tween 20, GPs were more effective at inhibiting AST from degradation during 30 days of storage at both 5 and 25 °C. However, GPs led to lower lipid digestion and AST bioaccessibility from nanoemulsions than did Tween 20. [ABSTRACT FROM AUTHOR]

In this study ginseng saponins (GS) were used as natural emulsifiers to formulate and stabilize O/W nanoemulsions loaded with astaxanthin (AST). GS were found to be highly effective at reducing the interfacial tension at the soybean oil–water interfaces, and were capable of producing nano-scaled droplets ( d 4,3  ≈ 125 nm) using a high-pressure homogenizer. The droplet size of the nanoemulsions decreased with increasing emulsifier concentration and homogenization pressure. The nanoemulsions were stable without droplet coalescence against thermal treatment (30–90 °C, 30 min), and over a narrow range of pH values (7–9). GS-coated droplets were unstable in acidic conditions (pH 3–6) and in the presence of salt (>25 mM NaCl). The formulated nanoemulsions showed slight change in d 4,3 during 15 days of storage at 5, 25 and 40 °C. However, the chemical stability strongly depended on the storage temperature, with the lowest level of AST retained in nanoemulsions stored at higher temperature. [ABSTRACT FROM AUTHOR]

In this work, we compared the formulation, stability and bioaccessibility of ergocalciferol nanodispersions using modified lecithin (ML) and sodium caseinate (SC) as natural emulsifiers. The mean particle size of nanodispersions stabilized by ML (56 nm) was much smaller than those stabilized by SC (112 nm). The ML-stabilized nanodispersions were stable over a wide range of pH, NaCl concentrations and heating, but became unstable with slight increase in particle size when exposed to CaCl 2 solution. In comparison, SC-stabilized nanodispersions were relatively unstable to particles aggregation at pH 4 and 5, CaCl 2 addition and heating. Long-term stability for ergocalciferol were observed in both ML- and SC-stabilized nanodispersions. In the absence of milk, the ergocalciferol bioaccessibility was strongly dependent on the emulsifier type, with ML providing much higher bioaccessibility than SC. During in vitro gastrointestinal digestion, the incorporation of milk into nanodispersions could increase the bioaccessibility and stability for ergocalciferol. [ABSTRACT FROM AUTHOR]

In the study, we investigated the effect of emulsifiers with different stabilizing mechanisms on the formulation and stability of ergocalciferol loaded oil-in-water (O/W) emulsions. O/W emulsion stabilized by modified lecithin (ML; electrostatic stabilization), sodium caseinate (SC; electrosteric stabilization) or decaglycerol monooleate (MO-7S; steric stabilization) were formulated using high-pressure homogenization. The Sauter mean diameter ( d 3,2 ) of emulsions produced by ML, SC and MO-7S were 126 ± 1, 127 ± 4 and 138 ± 3 nm, respectively. The stability of resulting emulsions was evaluated when they exposed to different environmental stresses and during 30 days of storage at 25 and 55 °C. Results showed that the emulsions prepared by MO-7S or ML were stable against a wide range of pH (2–8), while SC-stabilized emulsions showed instability with extensive droplet aggregation at pH 4 or and 5. Only ML-stabilized emulsions showed droplet growth due to coalescence when treated at high NaCl concentration (300–500 mM). In the absence of glucose, SC-stabilized O/W emulsions showed better freeze-thaw stability, in comparison to those formed with ML or MO-7S emulsifiers. The emulsion produced by ML was found to be stable to droplet aggregation at heating temperatures (80–120 °C) for 1 h. All the O/W emulsions stored at 25 °C showed good physical and chemical stability. However, the chemical stability of ergocalciferol in emulsion system decreased in order of ML > MO-7S ≫ SC during storage at 55 °C for a period of 30 days. These findings provide valuable information for the development of nanoemulsion-based delivery system applied in food and beverage products. [ABSTRACT FROM AUTHOR]

Transcatheter arterial chemoembolization (TACE) is widely used for the treatment of advanced hepatocellular carcinoma (HCC). However, the long-term hypoxic microenvironment caused by TACE seriously affects the therapeutic effect of TACE. HIF-2α plays a crucial role on the chronic hypoxia process, which might be an ideal target for TACE therapy. Herein, a multifunctional polyvinyl alcohol (PVA)/hyaluronic acid (HA)-based microsphere (PT/DOX-MS) co-loaded with doxorubicin (DOX) and PT-2385, an effective HIF-2α inhibitor, was developed for enhanced TACE treatment efficacy. In vitro and in vivo studies revealed that PT/DOX-MS had a superior ability to treat HCC by blocking the tumor cells in G2/M phase, prompting cell apoptosis, and inhibiting tumor angiogenesis. The antitumor mechanisms of PT/DOX-MS were possibly due to that the introduction of PT-2385 could effectively inhibit the expression level of HIF-2α in hypoxic HCC cells, thereby down-regulating the expression levels of Cyclin D1, VEGF and TGF-α. In addition, the combination of DOX and PT-2385 could jointly inhibit VEGF expression, which was another reason accounting for the combined anti-cancer effect of PT/DOX-MS. Overall, our study demonstrated that PT/DOX-MS is a promising embolic agent for enhanced HCC treatment via the combined effect of hypoxia microenvironment improvement, chemotherapy, and embolization. [ABSTRACT FROM AUTHOR]

• 1. A novel abiotic polymer chemistry in living system. • 2. Clustering cell-surface receptors and thus manipulating cell fate by a NIR-light controlled polymerization. • 3. The bio-application of in-situ synthesized nano-materials has been expanded. • 4. A drug-free macromolecular anti-tumor therapeutic. Schematic illustration of the NIR up-conversion controlled, in-situ synthesized, drug-free macromolecular therapeutic for anti-tumor therapy. [Display omitted] Drug-free macromolecular therapeutics induce cell apoptosis by clustering non-internalizing cell-surface receptors, which has demonstrated great promise in tumor therapy, particularly in terms of non-specific toxicities when compared with low-molecular-weight drugs. However, most reported drug-free macromolecular therapeutics involve a 'two-step' administration manner and the in vivo study is scarce, likely imposing difficulties on in vivo application. Here, we in-situ synthesized a drug-free macromolecular therapeutic in living system by near-infrared up-conversion controlled cross-linking. Taking CD20 receptor-positive B-cell lymphoma as the model disease, poly(2-hydroxyethyl methacrylate) with pendants of cinnamate groups (CA) were first introduced onto the surface of up-conversion nanoparticles (UCNP), which were then functionalized with anti-CD20 aptamer to give Apt-pHEMA(CA)@UCNP. After a local or systemic administration of Apt-pHEMA(CA)@UCNP plus the local application of 980-nm NIR laser, the growth of tumor was significantly suppressed with no detectable toxicities. Exploring the superior anti-tumor efficiency of Apt-pHEMA(CA)@UCNP combined with 980-nm NIR laser, we found that Apt-pHEMA(CA)@UCNP bound onto the surface of tumor cell by the interaction between CD20 receptors and anti-CD20 aptamers, without causing any reduction on cell viability. While after the local application of 980-nm laser, UCNP harvested the NIR light and converted it into UV light, which resulted in the cross-linking of CA groups, thus the clustering of CD20 receptors and cell apoptosis. We believe this NIR up-conversion controlled, in-situ synthesized drug-free macromolecular therapeutic expands the repertoire of macromolecular drugs and opens a new avenue for tumor therapy. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a life-threatening disease without effective treatment. The utilization of curcumin (Cur) for the treatment of AKI is still facing challenges due to its poor water-solubility and low bioavailability. Herein, kidney-targeted octenyl succinic anhydride-grafted fucoidan loaded with Cur (OSA-Fucoidan/Cur) was fabricated for synergistic treatment of AKI. It was found that OSA-Fucoidan/Cur micelles had a sustained drug release behavior and excellent physicochemical stability. Cellular uptake studies demonstrated that the specific binding between fucoidan and P-selectin overexpressed on H 2 O 2 -stimulated HUVECs contributed to the higher internalization of OSA-Fucoidan/Cur micelles by the cells. In addition, OSA-Fucoidan micelles exhibited an ideal kidney-targeted characteristic in lipopolysaccharide (LPS)-induced AKI mice. In vivo studies showed that the combination of Cur and OSA-Fucoidan endowed the OSA-Fucoidan/Cur micelles with synergistically anti-inflammatory and antioxidant abilities, thereby largely enhancing the therapeutic efficacy of AKI. Therefore, OSA-Fucoidan/Cur micelles may represent a potential kidney-targeted nanomedicine for effective treatment of AKI. Novel P-selectin targeted OSA-Fucoidan/Cur micelles were fabricated for synergetic treatment AKI. OSA-Fucoidan/Cur micelles were highly accumulated in the injured kidney due to their P-selectin targeting ability; the combination of Cur and fucoidan-based polymeric micelles endows OSA-Fucoidan/Cur micelles with synergistic anti-inflammatory and anti-oxidant abilities, thereby achieving enhanced treatment of AKI. [Display omitted] [ABSTRACT FROM AUTHOR]

Oxidative stress is an important pathological mechanism for acute kidney injury (AKI). SS-31, as a mitochondria-targeted peptide with strong antioxidant activity, is a good candidate for the treatment of AKI. However, an efficient treatment of AKI requires frequent administration of SS-31, which is due to its poor specific biodistribution and low delivery efficiency. To overcome these deficiencies, we designed pH-responsive and AKI-kidney targeted nanopolyplexes (NPs) for effectively delivering SS-31, which is new frontier for formulation of HA and CS. NPs are electrostatically complexed using anionic hyaluronic acid and cationic chitosan as materials, which could increase the accumulation in injured areas and uptake into CD44-overexpressed cells. Electrostatic balance of NPs is broken in low pH environment of lysosomes to allow SS-31 releasing and subsequently targeting to mitochondria to represent therapeutic effect. In vitro studies indicate that NPs exhibited higher antioxidative and antiapoptotic effects as compared with free SS-31. AKI mouse model suggests that NPs have significantly higher therapeutic efficiency than bare SS-31. It was found that NPs had excellent ability to decrease oxidative stress, protect mitochondrial structure, reduce inflammatory response, reduce apoptosis and necrosis of tubular cells after intravenious administration. Overall, the results suggest that the NPs have significant potential to enhance the specific biodistribution and delivery of SS-31, therefore have good effects on reducing oxidative stress and inflammation, preventing tubular apoptosis and necrosis. We believe NPs are effective delivery system for AKI treatment in clinical application. [ABSTRACT FROM AUTHOR]

Abstract The formulation of complex coacervates between gelatin and octenyl succinic anhydride (OSA) modified kudzu starch was investigated by turbidimetric analysis as a function of pH and ratio of gelatin and OSA-modified kudzu starch. The interaction between gelatin and OSA-modified kudzu starch yielded a dense liquid coacervate phase, leading to phase separation, and the optimum conditions for their coacervation was pH 6.0 and the mixed ratio of 1:1 (w/w). To characterize the complex coacervates, differential scanning calorimetry (DSC) thermograms revealed that the endothermic peak temperature of coacervates increased due to the interaction between these two polymers, and scanning electron microscopy (SEM) suggested that gelatin and OSA-modified kudzu starch were interconnected, forming a network structure through electrostatic attraction. Moreover, Fourier transform infrared spectroscopy (FT-IR) spectra indicated that coacervates were formulated between the carboxyl groups of OSA-modified kudzu starch and the amino groups of gelatin. The astaxanthin (AST) extract was encapsulated in complex coacervates and its stability was observed during 10 days of storage time. The results revealed higher retention of AST encapsulated in complex coacervates in comparison with gelatin. Graphical abstract Image Highlights • Complex coacervates were formulated from gelatin and OSA-modified kudzu starch. • The optimized complexation includes pH of 6.0 with mixing ratio of 1:1. • The endothermic peak temperature of complex coacervates increased. • -COO- groups of OSA-modified kudzu starch interacted with -NH 3 + groups of gelatin. • AST encapsulated by coacervates expressed better stability against degradation. [ABSTRACT FROM AUTHOR]

Kudzu starch esterified with octenyl succinic anhydride (OSA) was used as a food-grade emulsifier to formulate O/W emulsions. In addition, the difference between the physicochemical properties and emulsifying ability of native kudzu starch and those of OSA-modified kudzu starch was investigated. Granules of the OSA-modified kudzu starches increased in size after gelatinization. The interfacial tension between soybean oil and gelatinized OSA-modified kudzu starch was lower than that of kudzu starch. The droplet size of O/W emulsions decreased to 186 nm at 100 MPa after three passes. The emulsions stabilized using gelatinized OSA-modified kudzu starch were less stable when exposed to different ionic strengths (100 mM to 500 mM NaCl), than when exposed to different pH levels (2–8). The results of oil droplet size and confocal laser scanning microscopy analysis indicated that emulsions containing 2–5% OSA-modified kudzu starch remained stable at room temperature for 30 days. [ABSTRACT FROM AUTHOR]

Transarterial chemoembolization (TACE) is an important approach for the treatment of unresectable hepatocellular carcinoma (HCC). However, the lactic acid-induced acidic tumor microenvironment (TME) may reduce the therapeutic outcome of TACE. Herein, monodispersed gelatin microspheres loaded with calcium carbonate nanoparticles (CaNPs@Gel-MS) as novel embolic agents were prepared by a simplified microfluidic device. It was found that the particle size and homogeneity of as-prepared CaNPs@Gel-MS were strongly dependent on the flow rates of continuous and dispersed phases, and the inner diameter of syringe needle. The introduction of CaNPs provided the gelatin microspheres with an enhanced ability to encapsulate the chemotherapeutic drug of DOX, as well as a pH-responsive sustained drug release behavior. In vitro results revealed that CaNPs@Gel-MS could largely increase the cellular uptake and chemotoxicity of DOX by neutralizing the lactic acid in the culture medium. In addition, CaNPs@Gel-MS exhibited an excellent and persistent embolic efficiency in a rabbit renal model. Finally, we found that TACE treatment with DOX-loaded CaNPs@Gel-MS (DOX/CaNPs@Gel-MS) had a much stronger ability to inhibit tumor growth than the DOX-loaded gelatin microspheres without CaNPs (DOX@Gel-MS). Overall, CaNPs@Gel-MS could be a promising embolic microsphere that can significantly improve anti-HCC ability by reversing lactic acid-induced chemotherapy resistance during TACE treatment. [Display omitted] • Monodisperse CaCO 3 nanoparticle-loaded gelatin microsphere (CaNPs@Gel-MS) was prepared. • CaNPs@Gel-MS was highly effective at encapsulating doxorubicin (DOX). • CaNPs@Gel-MS could reverse lactic acid-induced resistance of DOX. • CaNPs@Gel-MS exhibited an excellent and persistent embolic efficiency in vivo. • DOX/CaNPs@Gel-MS had a stronger TACE efficacy than DOX@Gel-MS. [ABSTRACT FROM AUTHOR]

Liver cancer is a kind of malignant tumor with poor sensitivity to chemotherapy. It is urgent to investigate approaches to improve the outcome of chemotherapy. KDM5A has been reported to be an oncogene in various cancers and is associated with drug resistance. However, the functions of KDM5A in chemotherapeutic sensitivity of liver cancer not been well illustrated. In this study, we found that KDM5A was upregulated in liver cancer tissue and cell lines. KDM5A knockdown using a gene interference strategy suppressed the growth of liver cancer in vitro and in vivo. CPI-455, a pharmacological inactivation of KDM5A enhanced the cytotoxicity of cisplatin (CDDP) in liver cells. CPI-455 and CDDP cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that knockdown or inactivation of KDM5A resulted in the downregulation of ROCK1, an oncogene regulating the activation of the PTEN/AKT signaling pathway. In particular, overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and CDDP cotreatment. In HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP treatment alone. In conclusion, this study suggested that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to CDDP by modulating the ROCK1/PTEN/AKT signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: To construct a precise prediction model of preoperative magnetic resonance imaging (MRI)-based nomogram for aggressive intrasegmental recurrence (AIR) of hepatocellular carcinoma (HCC) patients treated with radiofrequency ablation (RFA).Methods: Among 891 patients with HCC treated by RFA, 22 patients with AIR and 36 patients without AIR (non-AIR) were finally enrolled in our study, and each patient was followed up for more than 6 months to determine the occurrence of AIR. The laboratory indicators and MRI features were compared and assessed. Preoperative contrast-enhanced T1-weighted images (CE-T1WI) were used for radiomics analysis. The selected clinical indicators and texture features were finally screened out to generate the novel prediction nomogram.Results: Tumor shape, ADC Value, DWI signal intensity and ΔSI were selected as the independent factors of AIR by univariate and multivariate logistic regression analysis. Meanwhile, two radiomics features were selected from 396 candidate features by LASSO (P < 0.05), which were further used to calculate the Rad-score. The selected clinical factors were further integrated with the Rad-score to construct the predictive model, and the AUCs were 0.941 (95% CI: 0.876-1.000) and 0.818 (95% CI: 0.576-1.000) in the training (15 AIR and 25 non-AIR) and validation cohorts (7 AIR and 11 non-AIR), respectively. The AIR predictive model was further converted into a novel radiomics nomogram, and decision curve analysis showed good agreement.Conclusions: The predictive nomogram integrated with clinical factors and CE-T1WI -based radiomics signature could accurately predict the occurrence of AIR after RFA, which could greatly help individualized evaluation before treatment. [ABSTRACT FROM AUTHOR]

In this study, we investigated the formulation and stability characteristics of monodisperse oil-in-water (O/W) emulsions encapsulating fucoxanthin using straight-through microchannel emulsification (MCE). Monodisperse O/W emulsions stabilized by hydrophilically modified lecithin (ML), whey protein isolate (WPI), or polyoxyethylene (20) sorbitan monolaurate (Tw20) were stably formulated using straight-through MCE. The resulting emulsions maintained the droplet sizes steadily at 30.3 ± 0.2 μm (ML), 32.3 ± 0.1 μm (WPI) and 29.0 ± 0.8 μm (Tw20) and the relative span factor (RSF) < 0.5 after 30 days storage at 25 °C. The fucoxanthin retention (RT f) in the collected emulsions, decreased from 100% to 44.3 ± 0.1% (ML), 90.7 ± 5.4% (WPI) and 51.4 ± 10.6% (Tw20) after storage. Subsequently, we compared the characteristics of O/W emulsions which were formulated by 1 wt% Tw20 using high-pressure homogenization (HPH) and MCE under the same storage and digestion conditions. After 15 days storage at 4, 25 and 50 °C, all emulsions revealed good physical stability, and there was no drastic change in the droplet sizes. In terms of chemical stability, MCE was pronouncedly better than HPH at the same level of storage temperature. In contrast, the free fatty acids (FFAs) release and fucoxanthin bioaccessibility in emulsions using HPH were significantly higher than MCE. The findings of our study give useful information for food and pharmaceutical industries which express more concern about the natural bioactive compounds for usage. Image 1 • Fucoxanthin was successfully encapsulated into emulsions using HPH and MCE. • Operation parameters have crucial impacts on the droplet generation using MCE. • Emulsions using MCE exhibited good physical and chemical stabilities. • MCE was better than HPH in chemical stabilities of emulsions during the long-term storage. • HPH was higher than MCE in the FFAs released and bioaccessibility of fucoxanthin. [ABSTRACT FROM AUTHOR]

Abbreviations: DPPC, dipalmitoyl phosphatidylcholine; SPC, hydrogenated soybean phosphatidylcholine; SIN, sinomenine hydrochloride; SIN-TSL, SIN-load thermosensitive liposomes; RA, rheumatoid arthritis; Chol, cholesterol. The conventional medications are still facing a huge challenge for the treatment of rheumatoid arthritis (RA). Thus, looking for an effective therapy of RA has became an urgent issue nowadays. In this study, a novel thermosensitive liposome loaded with sinomenine hydrochloride (SIN-TSL) was developed by a pH gradient method. The SIN-TSL had a mean particle size of around 100 nm, and an high entrapment efficiency and drug loading capacity. The results also suggested that SIN-TSL had a thermosensitive drug release behaviour, with the drug release rate at 43 °C was much faster than the one at 37 °C. The SIN-TSL could be effectively taken up by lipopolysaccharide-activated HUVECs, without any cytotoxicity was observed. In addition, both in vitro and in vivo studies indicated that the SIN-TSL combined with microwave hyperthermia exhibited superior anti-rheumatoid arthritis effect. Overall, these results suggest that SIN-loaded thermosensitive liposomes combined with microwave hyperthermia could provide an optional strategy for alleviating the clinical symptoms of RA. [ABSTRACT FROM AUTHOR]