Huibi Xu

Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi

Free radical scavenging and antioxidant activities of baicalein, baicalin, wogonin and wogonoside, the four major flavonoids in the radix of Scutellaria baicalensis Georgi, were examined in different systems. ESR results showed that baicalein and baicalin scavenged hydroxyl radical, DPPH radical and alkyl radical in a dose-dependent manner, while wogonin and wogonoside showed subtle or no effect on these radicals. Ten micromol/l of baicalein and baicalin effectively inhibited lipid peroxidation of rat brain cortex mitochondria induced by Fe(2+)-ascorbic acid, AAPH or NADPH, while wogonin and wogonoside showed significant effects only on NADPH-induced lipid peroxidation. In a study on cultured human neuroblastoma SH-SY5Y cells system, it was found that 10 micromol/l of baicalein and baicalin significantly protected cells against H(2)O(2)-induced injury. Baicalein was the most effective antioxidant among the four tested compounds in every system due to its o-tri-hydroxyl structure in the A ring. Compared with a well-known flavonoid, quercetin, the antioxidant activity of baicalein was lower in DPPH or AAPH system, but a little higher in those systems which might associate with iron ion. These results suggest that flavonoids in the radix of Scutellaria baicalensis with o-di-hydroxyl group in A the ring, such as baicalein and baicalin, could be good free radical scavengers and might be used to cure head injury associated with free radical assault.

Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure.

The present study investigated the penetration and potential toxicity of titanium dioxide (TiO(2)) nanoparticles following its dermal exposure in vitro and in vivo. In vitro, after exposure to isolated porcine skin for 24h, titanium dioxide nanoparticles of carious sizes cannot penetrate through stratum corneum. Interestingly, when studied in vivo, quite different results were obtained. After topically applied on pig ear for 30 days, TiO(2) nanomaterials (4 nm and 60 nm) can penetrate through horny layer, and be located in deep layer of epidermis. Furthermore, after 60 days dermal exposure in hairless mice, nano-TiO(2) particles can penetrate through the skin, reach different tissues and induce diverse pathological lesions in several major organs. Notably, P25 (21 nm) TiO(2) nanomaterials shows a wider tissue distribution, and can even be found in the brain without inducing any pathological changes. Among all of the organs examined, the skin and liver displayed the most severe pathological changes that correspond to the significant changes in SOD and MDA levels. These results suggest that the pathological lesions are likely to be mediated through the oxidative stress induced by the deposited nanoparticles. Accordingly, the collagen content expressed as HYP content are also significantly reduced in mouse skin samples, indicating that topically applied nano-TiO(2) in skin for a prolonged time can induce skin aging. Altogether, the present study indicates that nanosize TiO(2) may pose a health risk to human after dermal exposure over a relative long time period.

A new solid self-microemulsifying formulation prepared by spray-drying to improve the oral bioavailability of poorly water soluble drugs.

The objectives of the present work were, first, to develop a new solid self-microemulsifying drug delivery system (SMEDDS) for oral poorly water-soluble drugs such as nimodipine; and second, to evaluate its oral bioavailability in healthy rabbits. The liquid SMEDDS consisted of ethyl oleate, Labrasol, Cremophor RH 40 and nimodipine. The solid SMEDDS was prepared by spray-drying the liquid SMEDDS in a laboratory spray dryer, using dextran as solid carrier. The imaging of TEM and photo correlation spectroscopy revealed no difference in the droplet size of reconstituted microemulsion between both SMEDDS. Solid state characterization of the solid SMEDDS was performed by SEM, DSC, and X-ray powder diffraction. The same dose of nimodipine in the solid SMEDDS and in the liquid SMEDDS resulted in similar AUC and C(max) values, but the maximum absorption was retarded by the solid SMEDDS. AUC and C(max) after oral administration of the solid SMEDDS were 2.6- and 6.6-fold higher, respectively, compared with those of the conventional tablet. These results demonstrate that the solid SMEDDS may preserve an improved bioavailability with releasing microemulsion lipid droplets from the formulation in vivo. Thus, this solid self-microemulsifying system may provide a useful solid dosage form for oral poorly water-soluble drugs.

Role of cellular uptake in the reversal of multidrug resistance by PEG-b-PLA polymeric micelles.

Understanding the processes involved in the cellular uptake of nanoparticles is critical for developing effective nano drug delivery systems. In this paper we found that PEG-b-PLA polymeric micelles firstly interacted with cell membrane using atomic force microscopy (AFM) and then released their core-loaded agents into the cell membrane by fluorescence resonance energy transfer (FRET). The released agents were internalized into the cells via lipid raft/caveolae-mediated endocytosis using total internal reflection fluorescence microscopy (TIRFM) and endocytic inhibitors. Further studies revealed that paclitaxel (PTX)-loaded PEG-b-PLA micelles (M-PTX) increased the cellular accumulation of PTX in PTX-resistant human ovarian cell line A2780/T which resulted in more apoptosis as measured by flow cytometry and the cleavage of poly (ADP-ribose) polymerase (PARP) compared with free PTX. PEG-b-PLA micelles inhibited P-glycoprotein (Pgp) function and Pgp ATPase activity but had no effect on Pgp protein expression. The membrane microenvironment studies showed that PEG-b-PLA micelles induced cell membrane depolarization and enhanced membrane microviscosity. These results suggested that PEG-b-PLA micelles might inhibit Pgp function to reverse multidrug resistance (MDR) via interaction with cell membrane to affect the membrane microenvironment. This study provides a foundation for understanding the mechanism of reversing MDR by nanoparticles better and designing more effective nano drug carriers.

Iontophoresis-driven penetration of nanovesicles through microneedle-induced skin microchannels for enhancing transdermal delivery of insulin

The transdsermal delivery of insulin remains a significant challenge due to low permeation rates at therapeutically useful rates. We report unilamellar nanovesicles with membrane thickness of 3-5 nm and entrapment efficiency of 89.05+/-0.91%, which can be driven by iontophoresis for enhancing transdermal delivery of insulin through microneedle-induced skin microchannels. The permeation rates of insulin from positive nanovesicles driven by iontophoresis through skins with microneedle-induced microchannels were 713.3 times higher than that of its passive diffusion. The in vivo studies show that the blood glucose levels of diabetic rats induced by the positive nanovesicles driven by iontophoresis through skins with microneedle-induced microchannels are 33.3% and 28.3% of the initial levels at 4 and 6 h, which are comparable to those induced by subcutaneous injection of insulin. The fluorescence imaging validated the penetration of insulin from the nanovesicles driven by iontophoresis through skins with microchannels. The nanovesicles with charges show significant permeation ability with the assistance of physical devices including microneedles and iontophoresis. This approach offers a new strategy for non-invasive delivery of peptides with large molecular weights using nanovesicles.

Investigation of the carbopol gel of solid lipid nanoparticles for the transdermal iontophoretic delivery of triamcinolone acetonide acetate

The purpose of this study was to investigate solid lipid nanoparticles (SLN) hydrogel for transdermal iontophoretic drug delivery. Triamcinolone acetonide acetate (TAA), a glucocorticoids compound, was employed as the model drug. SLN containing the drug triamcinolone acetonide acetate (TAA-SLN) and their carbopol gel with stable physicochemical properties were prepared. The use of TAA-SLN carbopol gel as a vehicle for the transdermal iontophoretic delivery of TAA was evaluated in vitro using horizontal diffusion cells fitted with porcine ear skin. We found that the TAA-SLN gel possessed good stability, rheological properties, and high electric conductance. Transdermal penetration of TAA from TAA-SLN gel cross the skin tissue was significantly enhanced by iontophoresis. The enhancement of the cumulative penetration amount and the steady-state penetration flux of the penetrated drug were related to the particle size of TAA-SLN and the characteristics of the applied pulse electric current, such as density, frequency, and on/off interval ratio. These results indicated that SLN carbopol gel could be used as a vehicle for transdermal iontophoretic drug delivery under suitable electric conditions.

Hydrogel-thickened nanoemulsion system for topical delivery of lipophilic drugs

In this work, a hydrogel-thickened nanoemulsion system (HTN) with powerful permeation ability, good stability and suitable viscosity was investigated for topical delivery of active molecules. HTN was prepared to deliver an oily mixture of 5% camphor, 5% menthol and 5% methyl salicylate for topical therapy of arthritis, minor joint and muscle pain using soybean oil as the oil phase, soybean lecithin, Tween 80 and poloxamer 407 as the surfactants, propylene glycol as the cosurfactant, carbomer 940 as a thickening agent. The HTN system was found to combine the o/w microstructure of nanoemulsion with the gel network of hydrogel and had a suitable viscosity of 133.2PaS. The system had small average diameters and good long-term stability. The abilities of HTN to deliver the high amounts of camphor, menthol and methyl salicylate were evaluated using the in vitro permeation studies. The permeation rates of camphor, menthol and methyl salicylate from the optimal HTN formulation were 138.0+/-6.5, 63.6+/-3.3, 53.8+/-3.2 microg cm(-2) h(-1) and showed the significant advantages over the control gel. The HTN with good stability and powerful permeation enhancing ability and suitable viscosity might be a promising prospective carrier for topical delivery of lipophilic drugs.

A polysaccharide-protein complex from Lycium barbarum upregulates cytokine expression in human peripheral blood mononuclear cells

The production of cytokine is a key event in the initiation and regulation of an immune response. Many compounds are now used routinely to modulate cytokine production, and therefore the immune response, in a wide range of diseases, such as cancer. Interleukin-2 and tumor necrosis factor-alpha are two important cytokines in antitumor immunity. In this study, the effects of Lycium barbarum polysaccharide-protein complex (LBP(3p)) on the expression of interleukin-2 and tumor necrosis factor-alpha in human peripheral blood mononuclear cells were investigated by reverse transcription polymerase chain reaction (RT-PCR) and bioassay. Administration of LBP(3p) increased the expression of interleukin-2 and tumor necrosis factor-alpha at both mRNA and protein levels in a dose-dependent manner. The results suggest that LBP(3p) may induce immune responses and possess potential therapeutic efficacy in cancer.

Lactoferrin-conjugated superparamagnetic iron oxide nanoparticles as a specific MRI contrast agent for detection of brain glioma in vivo.

A specific contrast agent for magnetic resonance imaging (MRI) is crucial to brain tumor patients for the surgical operation or the postoperative radiology. This study explored lactoferrin-conjugated superparamagnetic iron oxide nanoparticles (Lf-SPIONs) as an MRI contrast agent for the detection of brain gliomas in vivo. The hydrodynamic diameter of about 75 nm, saturation magnetization of 51 emu/g Fe and T(2) relaxivity of 75.6 mM(-1)S(-1) of the Lf-SPIONs suggested its applicability for MRI. Using a rat model of C6 glioma, Lf-SPIONs provided a better picture or more sensitivity to depict brain glioma on MR images than that of SPIONs. Significantly enhanced T(2)-weighted images of brain glioma were documented in vivo with Lf-SPIONs until 48 h after injection. Moreover, Lf-SPIONs were clearly observed around vascular region of the tumor slices after 48 h. High level expression of Lf receptors was confirmed in brain tumor tissues by RT-PCR and Western Blot compared to normal brain tissues. These findings suggested that Lf-SPIONs could be potentially employed as a sensitive and specific MRI contrast agent in the diagnosis of brain glioma.

Nanocomposite‐Based Photodynamic Therapy Strategies for Deep Tumor Treatment

Photodynamic therapy (PDT), as an emerging clinically approved modality, has been used for treatment of various cancer diseases. Conventional PDT strategies are mainly focused on superficial lesions because the wavelength of illumination light of most clinically approved photosensitizers (PSs) is located in the UV/VIS range that possesses limited tissue penetration ability, leading to ineffective therapeutic response for deep-seated tumors. The combination of PDT and nanotechnology is becoming a promising approach to fight against deep tumors. Here, the rapid development of new PDT modalities based on various smartly designed nanocomposites integrating with conventionally used PSs for deep tumor treatments is introduced. Until now many types of multifunctional nanoparticles have been studied, and according to the source of excitation energy they can be classified into three major groups: near infrared (NIR) light excited nanomaterials, X-ray excited scintillating/afterglow nanoparticles, and internal light emission excited nanocarriers. The in vitro and in vivo applications of these newly developed PDT modalities are further summarized here, which highlights their potential use as promising nano-agents for deep tumor therapy.