Hyperoside Nanomicelles Alleviate Atherosclerosis by Modulating the Lipid Profile and Intestinal Flora Structure in High-Fat-Diet-Fed Apolipoprotein-E-Deficient Mice.

Atherosclerosis (AS) is a serious threat to human health and the main pathological basis of cardiovascular disease. Hyperoside (Hyp), a flavonoid found mainly in traditional Chinese herbs, can exert antitumor, anti-inflammatory, antioxidant, and cardiovascular-protective effects. Herein, we prepared hybrid nanomicelles (HFT) comprising Hyp loaded into pluronic F-127 and polyethylene glycol 1000 vitamin E succinate and assessed their effects on AS. To establish an AS model, apolipoprotein-E-deficient (ApoE-/-) mice were fed a high-fat diet. We then analyzed the effects of HFT on AS-induced changes in aortic tissues and metabolic markers, simultaneously assessing changes in gut flora community structure. In mice with AS, HFT significantly reduced the aortic plaque area; decreased levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, inflammatory factors, and inducible nitric oxide synthase (NOS); increased high-density lipoprotein cholesterol, endothelial NOS, superoxide dismutase, catalase, and glutathione levels; and promoted the proliferation of beneficial gut bacteria. HFT could regulate intestinal flora structure and lipid metabolism and inhibit inflammatory responses. These beneficial effects may be mediated by inhibiting nuclear factor kappa B signal activation, reducing inflammatory factor expression and improving gut microflora structure and dyslipidemia. The present study provides an empirical basis for the development and clinical application of new dosage forms of Hyp.

Butanol Extract of Acanthopanax senticosus (Rupr. et Maxim.) Harms Alleviates Atherosclerosis in Apolipoprotein E-Deficient Mice Fed a High-Fat Diet.

This study investigated the effect of butanol extract of AS (ASBUE) on atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. The mice were administered ASBUE (390 or 130 mg/kg/day) or rosuvastatin (RSV) via oral gavage for eight weeks. In ApoE-/- mice, ASBUE suppressed the abnormal body weight gain and improved serum and liver biochemical indicators. ASBUE remarkably reduced the aortic plaque area, improved liver pathological conditions, and lipid metabolism abnormalities, and altered the intestinal microbiota structure in ApoE-/- mice. In the vascular tissue of ASBUE-treated mice, P-IKKß, P-NFκB, and P-IκBα levels tended to decrease, while IκB-α increased in high fat-diet-fed atherosclerotic mice. These findings demonstrated the anti-atherosclerotic potential of ASBUE, which is mediated by the interaction between the gut microbiota and lipid metabolism and regulated via the Nuclear Factor-kappa B (NF-κB) pathway. This work paves the groundwork for subsequent studies to develop innovative drugs to treat atherosclerosis.

Comparison of whole-head and split-head design for the clinical evaluation of anti-dandruff shampoo efficacy.

OBJECTIVE: Dandruff is a common scalp condition that can be improved by regular use of shampoos containing anti-fungal actives. The efficacy of anti-dandruff shampoos can be assessed by measuring scalp flaking, one of the important dandruff symptoms. A randomized, double-blind trial is often used with one of two clinical designs: whole-head parallel design and split-head paired design. We aimed to explore the difference in product differentiation between these two designs using the same two test shampoos and the same scalp flaking assessment method (Total Weighted Head Score Adhered Flakes-TWHS AF). METHODS: A clinical study was conducted with a 2- to 3-week wash-out phase and a 4-week test phase, consisting of 2 cells: 120 subjects with whole-head parallel design, divided into 2 subgroups (1:1) using on-site controlled washing method (either wash their own hair at a study site, under the instruction of a study supervisor or wash their own hair at home, as per instructions, but without supervision) and 35 subjects with split-head paired design using salon-staff washing method. Both cells employed hair washing at frequency of three times a week and TWHS AF measurement once a week from the baseline assessment. RESULTS: Both designs gave similar differences in TWHS AF between products: 5.6 units (95% CI: 4.1-7.0 units) in whole-head design and 5.9 units (95% CI: 4.9-6.9 units) in split-head design. CONCLUSION: Split-head paired design shows a similar ability of detecting product difference as whole-head parallel design, whereas it is a choice of more efficient and more cost-effective, as only a quarter of the subjects are required to demonstrate the efficacy between anti-dandruff shampoos.

OBJECTIF: Les pellicules sont une affection courante du cuir chevelu qui peut être améliorée par l'utilisation régulière de shampooings contenant des principes actifs antifongiques. L'efficacité des shampooings antipelliculaires peut être évaluée en mesurant la desquamation du cuir chevelu, l'un des symptômes importants associés aux pellicules. Il est souvent fait recours à une étude randomisée et en double aveugle reposant sur l'une des deux conceptions cliniques suivantes: une conception parallèle portant sur la tête entière et une conception appariée par séparation de la surface de la tête. Nous avons cherché à étudier en quoi des produits se différenciaient entre ces deux conceptions, en utilisant les deux mêmes shampooings d'examen et la même méthode d'évaluation de la desquamation du cuir chevelu (score total pondéré des pellicules collées sur la tête [Total Weighted Head Score Adhered Flakes, TWHS AF]). MÉTHODES: Une étude clinique a été menée avec une fenêtre thérapeutique de deux à trois semaines et une phase d'examen de quatre semaines, composée de deux cellules: 120 sujets recrutés selon une conception parallèle portant sur la tête entière, répartis en deux sous-groupes (1:1), avec un lavage réalisé au centre d'après une méthode contrôlée (lavage par le sujet dans l'un des centres de l'étude, réalisé sous les instructions d'un superviseur de l'étude, ou lavage par le sujet à son domicile, en suivant les instructions, mais sans surveillance) et 35 sujets recrutés selon une conception appariée par séparation de la surface de la tête, avec un lavage réalisé selon la méthode employée par le personnel des salons de coiffure. Pour les deux cellules, le lavage des cheveux avait lieu à une fréquence de trois fois par semaine et le score TWHS AF était mesuré une fois par semaine à partir de l'évaluation de référence. RÉSULTATS: Les deux conceptions ont permis d'observer des différences similaires des scores TWHS AF entre les produits: 5,6 unités (IC à 95%: 4,1 à 7,0 unités) avec la conception portant sur la tête entière et 5,9 unités (IC à 95%: 4,9 à 6,9 unités) avec la conception par séparation de la surface de la tête. CONCLUSION: Par comparaison avec la conception parallèle portant sur la tête entière, la conception appariée par séparation de la surface de la tête montre une capacité de détection similaire de la différence entre les produits, mais constitue un choix plus efficace et plus rentable, car elle n'exige de démontrer l'efficacité entre les shampooings antipelliculaires que chez un quart des sujets.

Doxorubicin encapsulated in micelles enhances radiosensitivity in doxorubicin-resistant tumor cells.

To evaluate the efficacy of doxorubicin (DOX) loaded micelles in enhancing DOX radiosensitivity in DOX-resistant K562 tumor cells (K562/DOX cells), DOX loaded polyethylene glycol-polycaprolactone (PEG-PCL) copolymer micelles and pluronic 105 (P105) micelles, and composite micelles composed of PEG-PCL and P105 were prepared. By using MTT assay, soft agar cloning assays, confocal laser scanning microscopy, and flow cytometry analyses to evaluate the radiosensitivity of each compound, DOX loaded micelles were found to increase the radiosensitivity of K562/DOX cells, as revealed by a marked cellular uptake and its sustained, slower release than free DOX. The micelles encapsulating DOX significantly enhanced its cytotoxicity in K562/DOX cells. Combined treatment with the encapsulation of DOX in micelles and radiotherapy therefore warrants investigation in clinical trials as a potential anticancer strategy with increased efficacy and reduced side effects.

Doxorubicin-mediated radiosensitivity in multicellular spheroids from a lung cancer cell line is enhanced by composite micelle encapsulation.

BACKGROUND: The purpose of this study is to evaluate the efficacy of composite doxorubicinloaded micelles for enhancing doxorubicin radiosensitivity in multicellular spheroids from a non-small cell lung cancer cell line. METHODS: A novel composite doxorubicin-loaded micelle consisting of polyethylene glycolpolycaprolactone/Pluronic P105 was developed, and carrier-mediated doxorubicin accumulation and release from multicellular spheroids was evaluated. We used confocal laser scanning microscopy and flow cytometry to study the accumulation and efflux of doxorubicin from A549 multicellular spheroids. Doxorubicin radiosensitization and the combined effects of irradiation and doxorubicin on cell migration and proliferation were compared for the different doxorubicin delivery systems. RESULTS: Confocal laser scanning microscopy and quantitative flow cytometry studies both verified that, for equivalent doxorubicin concentrations, composite doxorubicin-loaded micelles significantly enhanced cellular doxorubicin accumulation and inhibited doxorubicin release. Colony-forming assays demonstrated that composite doxorubicin-loaded micelles are radiosensitive, as shown by significantly reduced survival of cells treated by radiation + composite micelles compared with those treated with radiation + free doxorubicin or radiation alone. The multicellular spheroid migration area and growth ability verified higher radiosensitivity for the composite micelles loaded with doxorubicin than for free doxorubicin. CONCLUSION: Our composite doxorubicin-loaded micelle was demonstrated to have radiosensitization. Doxorubicin loading in the composite micelles significantly increased its cellular uptake, improved drug retention, and enhanced its antitumor effect relative to free doxorubicin, thereby providing a novel approach for treatment of cancer.

Doxorubicin-loaded PEG-PCL copolymer micelles enhance cytotoxicity and intracellular accumulation of doxorubicin in adriamycin-resistant tumor cells.

BACKGROUND: Multidrug resistance remains a major obstacle to successful cancer chemotherapy. Some chemical multidrug resistance inhibitors, such as ciclosporin and verapamil, have been reported to reverse resistance in tumor cells. However, the accompanying side effects have limited their clinical application. In this study, we have developed a novel drug delivery system, ie, a polyethyleneglycol-polycaprolactone (PEG-PCL) copolymer micelle encapsulating doxorubicin, in order to circumvent drug resistance in adriamycin-resistant K562 tumor cells. METHODS: Doxorubicin-loaded diblock copolymer PEG-PCL micelles were developed, and the physicochemical properties of these micelles, and accumulation and cytotoxicity of doxorubicin in adriamycin-resistant K562 tumor cells were studied. RESULTS: Doxorubicin-loaded micelles were prepared using a solvent evaporation method with a diameter of 36 nm and a zeta potential of +13.8 mV. The entrapment efficiency of doxorubicin was 48.6% ± 2.3%. The micelles showed sustained release, increased uptake, and cellular cytotoxicity, as well as decreased efflux of doxorubicin in adriamycin-resistant K562 tumor cells. CONCLUSION: This study suggests that PEG-PCL micelles have the potential to reverse multidrug resistance in tumor cells.

Molecular mechanism study of chemosensitization of doxorubicin-resistant human myelogenous leukemia cells induced by a composite polymer micelle.

The present study was aimed to overcome the multidrug resistance (MDR) of tumor cells which accounts for the failure of clinical chemotherapy. A novel doxorubicin (DOX)-loaded composite micelle consisting of polyethylene glycol (PEG)-polycaprolactone (PCL)/Pluronic P105 has been developed and was proved to inhibit the drug resistance of human myelogenous leukemia (K562/ADR) cells. The modulation mechanism that DOX-loaded the composite micelle inhibited MDR was for the first time investigated at cell levels. Results indicated that the cytotoxicity in K562/ADR cells treated by DOX-loaded PEG-PCL/P105 composite micelle was about 4 times higher than DOX solution at 12 µg/mL of DOX. Confocal images showed that the DOX-loaded composite micelles gradually entered into cytoplasm and nucleus, and stayed in intracellular much longer than DOX solution. All the micelles (PEG-PCL micelle, P105 micelle and PEG-PCL/P105 composite micelle) did not change Pgp expression on the surface of K562/ADR cells. However, further study revealed that micelle containing of P105 (P105 or PEG-PCL/P105 composite micelle) significantly decreased ATP level, and consequently restricted the activity of Pgp by down-regulation of mitochondrial membrane potential. On the other hand, the PEG-PCL micelle had no effect on both mitochondrial membrane potential and ATP level of the K562/ADR cells, but its access to K562/ADR cells through endocytic pathway avoided the recognition of Pgp. The PEG-PCL/P105 composite micelle was designed based on the combination of P105-mediated down regulation of mitochondrial membrane potential the malignant cells and PEG-PCL-mediated internalization effect. Therefore, the novel composite micelle is a promising drug delivery system for anticancer drug to overcome MDR.

DOX-loaded PEG-PLGA and Pluronic copolymer composite micelles enhances cytotoxicity and the intracellular accumulation of drug in DOX-resistant tumor cells.

In the present study, doxorubicin (DOX) loaded polyethyleneglycol-poly (DL-lactic-co-glycolic acid) micelle as well as composite micelles composed polyethyleneglycol- poly(DL-lactic-co-glycolic acid) (PEG-PLGA) and Pluronic 105 (P105) were constructed. The micelles, with diameter around 106 nm and 85 nm respectively, were prepared by solvent evaporation method. The results showed that the encapsulation of DOX in micelles could significantly enhance its cytotoxicity in a DOX resistant tumor cell line, K562/DOX. The combination of PEG-PLGA and Pluronic further improved both the tumor-suppressive activity and the intracellular accumulation of DOX, indicating that the composite micelles would be potential to reverse the multidrug resistance in tumor cells.

[Progress in the study of micelle delivery system reversing multidrug resistance].

Multidrug resistance (MDR) of cancer cells to anti-tumor drugs remains a major impediment to successful chemotherapy. There has been an increasing interest in the studies of the mechanism and reverse of the MDR. Being a reliable and safe way to reverse MDR, drug delivery systems (DDS) such as micelle, liposome and nanoparticle, represent a promising prospect both in research and application in recent years. On the basis of recent studies, the effect and mechanism of micelles on reversing MDR are reviewed. And it is anticipated that DDS could contribute greatly to reversing MDR in the future.

A novel camptothecin derivative incorporated in nano-carrier induced distinguished improvement in solubility, stability and anti-tumor activity both in vitro and in vivo.

PURPOSE: An oil/water nanoemulsion was developed in the present study to enhance the solubility, stability and anti-tumor activity of a novel 10-methoxy-9-nitrocamptothecin (MONCPT). MATERIALS AND METHODS: MONCPT nanoemulsion was prepared using Lipoid E80 and cremophor EL as main emulsifiers by microfluidization. The droplet size of the nanoemulsion was measured by dynamic light scattering. In vitro drug release was monitored by membrane dialysis. Kinetics of MONCPT transformed into carboxylic salt was performed in phosphate buffer at different pH. Hemolysis of MONCPT nanoemulsion was conducted in rabbit erythrocytes. Solubilization character of MONCPT in nanoemulsion was experimented using Nile red as a solvatochromic probe. In vitro cytotoxicity of the nanoemulsion was measured in A549 and S180 cells using Sulforhodamine B protein stain method, and suppression rate of tumor growth was investigated in S180-bearing mice. The cell cycle effects of MONCPT nanoemulsion on S180 cells were analyzed by flow cytometry. Distribution of the nanoemulsion in A549 cells and S180-bearing mice were also investigated by fluorescence image. RESULTS: MONCPT is incorporated in the nanoemulsion in form of lactone with concentration of 489 microg/ml, more than 200 folds higher than that in water. Experiments using Nile red as a solvatochromic probe indicated that more MONCPT might be located in the interfacial surfactant layer of the nanoemulsion than that in discrete oil droplet or continuous aqueous phase. Nanoemulsion could release MONCPT in a sustained way, and it was further shown to notably postpone the hydrolysis of MONCPT with longer hydrolysis half-life time (11.38 h) in nanoemulsion at pH 7.4 than that of MONCPT solution (4.03 h). No obvious hemolysis was caused by MOCPT nanoemulsion in rabbit erythrocytes. MONCPT nanoemulsion showed a marked increase in cytotoxic activity, 23.6 folds and 28.6 folds in S180 cells and A549 cells respectively via arresting the cell at G2 phase, compared to that induced by MONCPT injection. It correlated well to the in vivo anti-tumor activity of MONCPT nanoemulsion with suppression rate of 93.6%, while that of MONCPT injection was only 24.2% at the same dosage. Moreover, nanoemulsion exhibited enhanced capability of delivering drug into malignant cell's nucleus in vitro and induced drug accumulation in tumor in S180-bearing mice using in vivo imaging. CONCLUSION: The nanoemulsion prepared exhibited an improved MONCPT solubility, stability and anti-tumor activity, providing a promising carrier for cancer chemotherapy using MONCPT.