Toxicity of single‐wall carbon nanotubes functionalized with polyethylene glycol in zebrafish (Danio rerio) embryos

Single‐wall carbon nanotubes functionalized with polyethylene glycol (SWCNT‐PEG) are promising materials for biomedical applications such as diagnostic devices and controlled drug‐release systems. However, several questions about their toxicological profile remain unanswered. Thus, the aim of this study was to investigate the action of SWCNT‐PEG in Danio rerio zebrafish embryos at the molecular, physiological and morphological levels. The SWCNT used in this study were synthesized by the high‐pressure carbon monoxide process, purified and then functionalized with distearoyl phosphatidylethanolamine block copolymer‐PEG (molecular weight 2 kDa). The characterization process was carried out with low‐resolution transmission electron microscopy, thermogravimetric analysis and Raman spectroscopy. Individual zebrafish embryos were exposed to the SWCNT‐PEG. Toxic effects occurred only at the highest concentration tested (1 ppm) and included high mortality rates, delayed hatching and decreased total larval length. For all the concentrations tested, the alkaline comet assay revealed no genotoxicity, and Raman spectroscopy measurements on the histological slices revealed no intracellular nanotubes. The results shown here demonstrate that SWCNT‐PEG has low toxicity in zebrafish embryos, but more studies are needed to understand what mechanisms are involved. However, the presence of residual metals is possibly among the primary mechanisms responsible for the toxic effects observed, because the purification process was not able to remove all metal contamination, as demonstrated by the thermogravimetric analysis. More attention must be given to the toxicity of these nanomaterials before they are used in biomedical applications. Copyright © 2016 John Wiley & Sons, Ltd.     

Distribution of single wall carbon nanotubes in the Xenopus laevis embryo after microinjection

Single wall carbon nanotubes (SWCNTs) are advanced materials with the potential for a myriad of diverse applications, including biological technologies and large‐scale usage with the potential for environmental impacts. SWCNTs have been exposed to developing organisms to determine their effects on embryogenesis, and results have been inconsistent arising, in part, from differing material quality, dispersion status, material size, impurity from catalysts and stability. For this study, we utilized highly purified SWCNT samples with short, uniform lengths (145 ± 17 nm) well dispersed in solution. To test high exposure doses, we microinjected > 500 µg ml^–1 SWCNT concentrations into the well‐established embryogenesis model, Xenopus laevis, and determined embryo compatibility and subcellular localization during development. SWCNTs localized within cellular progeny of the microinjected cells, but were heterogeneously distributed throughout the target‐injected tissue. Co‐registering unique Raman spectral intensity of SWCNTs with images of fluorescently labeled subcellular compartments demonstrated that even at regions of highest SWCNT concentration, there were no gross alterations to subcellular microstructures, including filamentous actin, endoplasmic reticulum and vesicles. Furthermore, SWCNTs did not aggregate and localized to the perinuclear subcellular region. Combined, these results suggest that purified and dispersed SWCNTs are not toxic to X. laevis animal cap ectoderm and may be suitable candidate materials for biological applications. Copyright © 2015 John Wiley & Sons, Ltd.     

Enhancement on oral absorption of paclitaxel by multifunctional pluronic micelles

The aim of the present study is to synthesize Pluronic F127-polyethylenimine-folate (PF127-PEI-FA) copolymer, construct a mixed micelle system with PF127-PEI-FA copolymer and Pluronic P123 (PP123) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel (PTX). The results of intestinal absorption revealed that the PTX-loaded micelles displayed superior permeability across intestinal barrier than free drug and PF127-PEI-FA/PP123 mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cytotoxicity and cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-glycoprotein (P-gp) and enhancement of the electrostatic interaction of positive micelles with the negative intestinal epithelial cells, thereby promoting the permeation across the intestinal wall. The presence of verapamil and Pluronic both improved the intestinal absorption of PTX, which further certified the effect of Pluronic on P-gp inhibition. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC_{0→36 h}) of PTX-loaded micelles was three times greater than the PTX solution (dissolved in a 50/50 (vol/vol) mixture of Cremophore EL/dehydrated ethanol) (p < 0.05). In general PF127-PEI-FA/PP123 mixed micelles were proved to be potential oral drug delivery system for PTX.     

九节龙皂苷Ⅰ聚合物载药胶束的制备及体外表征

目的制备九节龙皂苷Ⅰ普朗尼克F127载药胶束。方法采用成膜-水化法制备该胶束体系,通过正交实验优化处方,用透射电镜和激光粒子测定仪对胶束的粒径分布和形态进行表征,用透析法考察体外释药特征。结果最优处方制备的九节龙皂苷Ⅰ普朗尼克F127载药胶束的粒径为18.74nm,外观呈圆球形,包封率大于90%,较九节龙皂苷Ⅰ(ADS-Ⅰ)纯药具有显著的缓释效果。结论九节龙皂苷Ⅰ普朗尼克F127载药胶束的粒径小,包封率高,可显著增加所载药物的溶解性,且具有显著缓释作用,是1种具有应用前景的抗肿瘤药物给药系统。     

Formulation and in vivo assessment of terconazole-loaded polymeric mixed micelles enriched with Cremophor EL as dual functioning mediator for augmenting physical stability and skin delivery

The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 2³ full factorial design was performed using Design-Expert® software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98?±?0.40%) and a very small micellar size (33.23?±?8.00?nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ.     

Preparation of sodium cholate-based micelles through non-covalent ıbonding interaction and application as oral delivery systems for paclitaxel

In present study, two types of micelles based on sodium cholate (NaC) were prepared through non-covalent bonding interaction and the potential of micelles as oral drug delivery systems for paclitaxel (PTX) was evaluated. Pluronic–chitosan (F127–CS) and Pluronic–poly (acrylic acid) (F127–PAA) copolymers were synthesized. Electrostatic interaction and hydrogen bond were used to prepare F127–CS/NaC micelles and F127–PAA/NaC micelles, respectively. The physicochemical characteristics of micelles were determined. An average diameter of 67.5?nm and unimodal pattern of size distribution were observed for F127–CS/NaC micelles. While for F127–PAA/NaC micelles, an average diameter of 85.89?nm and non-unimodal pattern of size distribution were observed. The results revealed that F127–CS/NaC micelles were more integrated than F127–PAA/NaC micelles. Further experiments showed that the F127–CS/NaC micelles had a higher drug-loading content of 12.8% and a lower critical micelle concentration (CMC) of 2.5?×?10^?3?mol/L compared with F127–PAA/NaC micelles. In vitro cytotoxicity analysis demonstrated that the PTX-loaded F127–CS/NaC micelles were of great efficiency in inhibiting the growth of drug-resistant breast cancer MCF-7 cells (MCF-7/Adr). The intragastric administration of the PTX-loaded F127–CS/NaC micelles in rats provided a 4.33-fold higher absolute bioavailability compared to commercial Taxol®, indicating an efficient oral absorption of PTX delivered by micelles. These findings signify that F127–CS/NaC micelle may be a promising carrier for the delivery of PTX.     

Antifungal activity of human salivary mucin‐derived peptide,MUC7 12‐mer,in a murine model of oral candidiasis

Abstract: Previous studies have shown that peptides derived from the N‐terminal region of the low molecular mass human salivary mucin, MUC7, possess potent in vitro cidal activity against Candida albicans and other medically important fungi. MUC7 12‐mer (residues 40–51 of the parent MUC7) peptide, having the optimal size and a net charge of +6, was found to be anticandidal in human saliva (clarified and unclarified), and its candidacidal potency was found to be superior to that of histatin 5 12‐mer (Hsn5 12‐mer). We have, therefore, explored the candidacidal potency of MUC7 12‐mer (l and d isomers) and Hsn5 12‐mer peptides in vivo. In vitro killing assay was performed to establish killing activity of the peptides against C. albicans prior to in vivo experiments. A murine model of oral candidiasis that has the characteristics of oral thrush in humans was employed for the in vivo studies, based on a previous protocol. Upon candidal induction, antifungal treatment application using agents emulsified in Pluronic F127 was performed for six consecutive days. Amphotericin B and clotrimazole emulsified in the same delivery system were used as positive control drugs. Candidacidal efficacy was evaluated microbiologically and histopathologically. Results demonstrated a considerable reduction of fungal burden by the MUC7 12‐mer peptides (l and d ), comparable to control drugs, and this effect was statistically significant, unlike the effect seen with Hsn5 12‐mer. Murine oral candidiasis model employed in this study is suitable to test the candidacidal agents employing Pluronic F127. In conclusion, MUC7 12‐mer appears to be a promising candidate as an antifungal agent for oral candidiasis.     

Improving Protein Delivery from Microparticles Using Blends of Poly(DL lactide co-glycolide) and Poly(ethylene oxide)-poly(propylene oxide) Copolymers

Purpose. Microparticles containing ovalbumin as a model for protein drugs were formulated from blends of poly(DL lactide-co-glycolide) and poly(ethylene oxide)-poly(propylene oxide) copolymers (Pluronic). The objectives were to achieve uniform release characteristics and improved protein delivery capacity. Methods. The water- in oil -in oil emulsion/solvent extraction technique was used for microparticle production. Results. A protein loading level of over 40% (w/w) was attained in microparticles having a mean diameter of approximately 5 µm. Linear protein release profiles over 25 days in vitro were exhibited by certain blend formulations incorporating hydrophilic Pluronic F127. The release profile tended to plateau after 10 days when the more hydrophobic Pluronic L121 copolymer was used to prepare microparticles. A delivery capacity of 3 µg OVA/mg particles/ day was achieved by formulation of microparticles using a 1:2 blend of PLG:Pluronic F127. Conclusions. The w/o/o formulation approach in combination with PLG:Pluronic blends shows potential for improving the delivery of therapeutic proteins and peptides from microparticulate systems. Novel vaccine formulations are also feasible by incorporation of Pluronic L121 in the microparticles as a co-adjuvant.     

Surfactant effects on carbon nanotube interactions with human keratinocytes

Interactions of multiwalled carbon nanotubes (MWCNTs) with human epidermal keratinocytes (HEKs) were studied with respect to the effect of surfactant on dispersion of MWCNT aggregates and cytotoxicity. Our earlier studies had shown that the unmodified MWCNTs were localized within the cytoplasmic vacuoles of HEKs and elicited an inflammatory response. However, MWCNTs in solution tend to aggregate and, therefore, cells are exposed to large MWCNT aggregates. The purpose of this study was to find a surfactant that prevents the formation of large aggregates of MWCNTs without being toxic to the HEKs. HEKs were exposed to serial dilutions (10% to 0.1%) of L61, L92, and F127 Pluronic and 20 or 60 Tween for 24 hours. HEK viability, proportional to surfactant concentration, ranged from 27.1% to 98.5% with Pluronic F127; viability with the other surfactants was less than 10%. Surfactants dispersed and reduced MWCNT aggregation in medium. MWCNTs at 0.4 mg/mL in 5% or 1% Pluronic F127 were incubated with HEKs and assayed for interleukin 8 (IL-8). MWCNTs were cytotoxic to HEKs independent of surfactant exposure. In contrast, MWCNT-induced IL-8 release was reduced when exposed to 1% or 5% Pluronic F127 (P < .05). However, both MWCNTs and surfactant, alone or in combination, increased IL-8 release compared with control exposures at 12 and 24 hours. These results suggest that the surfactant-MWCNT interaction is more complex than simple dispersion alone and should be investigated to determine the mode of interaction.     

Adipocytes differentiation in the presence of Pluronic F127–coated carbon nanotubes

Carbon nanotubes are considered important nanodevices in biomedicine, and several applications in drug and gene delivery in different organs and tissues are presently under investigation. Among them very little attention has been dedicated to white adipose tissue (WAT), despite its wide distribution and endocrine role, which could potentially be used to release therapeutic agents. An important premise to use nanotubes in WAT is to determine their potential for toxicity on adipocytes. Here we show that Pluronic F127 (PF127)–coated multiwalled carbon nanotubes (MWCNTs) can be tolerated by NIH-3T3-L1 pre-adipocytes without affecting their growth. Moreover, the differentiation process of NIH-3T3-L1 pre-adipocytes to adipocytes is not compromised by the presence of 5 μg/mL MWCNTs in the medium. These results suggest that reasonable concentrations of PF127-MWCNTs are not toxic for adipocytes and do not interfere with their differentiation process.From the Clinical EditorThis study established that Pluronic F127 (PF127)–coated multiwalled carbon nanotubes (MWCNTs) are tolerated by NIH-3T3-L1 pre-adipocytes. The differentation of these pre-adipocytes is not compromised by the presence of 5 μg/mL MWCNTs, suggesting that these nanotubes are not toxic for adipocytes.     

Salinity‐dependent toxicity of water‐dispersible,single‐walled carbon nanotubes to Japanese medaka embryos

To investigate the effects of salinity on the behavior and toxicity of functionalized single‐walled carbon nanotubes (SWCNTs), which are chemical modified nanotube to increase dispersibility, medaka embryos were exposed to non‐functionalized single‐walled carbon nanotubes (N‐SWCNTs), water‐dispersible, cationic, plastic‐polymer‐coated, single‐walled carbon nanotubes (W‐SWCNTs), or hydrophobic polyethylene glycol‐functionalized, single‐walled carbon nanotubes (PEG‐SWCNTs) at different salinities, from freshwater to seawater. As reference nanomaterials, we tested dispersible chitin nanofiber (CNF), chitosan‐chitin nanofiber (CCNF) and chitin nanocrystal (CNC, i.e. shortened CNF). Under freshwater conditions, with exposure to 10 mg l⁻¹ W‐SWCNTs, the yolk sacks of 57.8% of embryos shrank, and the remaining embryos had a reduced heart rate, eye diameter and hatching rate. Larvae had severe defects of the spinal cord, membranous fin and tail formation. These toxic effects increased with increasing salinity. Survival rates declined with increasing salinity and reached 0.0% in seawater. In scanning electron microscope images, W‐SWCNTs, CNF, CCNF and CNC were adsorbed densely over the egg chorion surface; however, because of chitin's biologically harmless properties, only W‐SWCNTs had toxic effects on the medaka eggs. No toxicity was observed from N‐SWCNT and PEG‐SWCNT exposure. We demonstrated that water dispersibility, surface chemistry, biomedical properties and salinity were important factors in assessing the aquatic toxicity of nanomaterials. Copyright © 2016 John Wiley & Sons, Ltd.     

Effects of nanomaterial physicochemical properties on in vivo toxicity

It is well recognized that physical and chemical properties of materials can alter dramatically at nanoscopic scale, and the growing use of nanotechnologies requires careful assessment of unexpected toxicities and biological interactions. However, most in vivo toxicity concerns focus primarily on pulmonary, oral, and dermal exposures to ultrafine particles. As nanomaterials expand as therapeutics and as diagnostic tools, parenteral administration of engineered nanomaterials should also be recognized as a critical aspect for toxicity consideration. Due to the complex nature of nanomaterials, conflicting studies have led to different views of their safety. Here, the physicochemical properties of four representative nanomaterials (dendrimers, carbon nanotubes, quantum dots, and gold nanoparticles) as it relates to their toxicity after systemic exposure is discussed.     

An assay to determine the sensitive window of embryos to chemical exposure using Xenopus tropicalis

The frog embryo teratogenesis assay‐Xenopus (FETAX) is an established method to evaluate the developmental toxicity of chemicals. In FETAX, a 48 h continuous exposure is usually conducted when the X. tropicalis embryo is used as the test model. In the present study, we exposed X. tropicalis embryos to nine known teratogens for four separate 12‐h periods. The embryos showed great variations in response to nine tested compounds during different exposure periods. Based on the value of the score of malformations, the most sensitive 12 h exposure periods of embryos were significantly distinguished for all the compounds with the exception of NiCl₂. The embryos were the most sensitive to retinols (e.g. all‐trans‐retinoic acid and 9‐cis‐retinoic acid) during 0–12 h and to metal compounds (e.g. triphenlytin and CdCl₂) during a 24 to 36 h exposure period. In the further 3 h exposure experiment, the most sensitive period could only be determined for one of three tested compounds. Based on the present results, we proposed an assay to determine a 12 h sensitive window of embryos to chemical exposure using Xenopus tropicalis. Copyright © 2015 John Wiley & Sons, Ltd.     

Stable phosphatidylcholine-bile salt mixed micelles enhance oral absorption of paclitaxel: preparation and mechanism in rats

Abstract

The aim of this study is to prepare a stable phosphatidylcholine/bile salt micelles with Pluronic F127-polyethylenimine conjugates (F127-PEI), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), soybean phosphatidylcholine (SPC) and sodium cholate (NaC) and to elucidate the effects and possible mechanism of micelle components on the intestinal absorption of paclitaxel (PTX) in rats. The results of intestinal absorption revealed that the PTX in SPC/NaC micelles displayed superior permeability across intestinal barrier than free drug and PTX in TPGS/SPC/NaC and F127-PEI/TPGS/SPC/NaC mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-gp and enhancement of the drug transportation across the unstirred water layer to the endothelial lining, thereby promoting the permeation across the intestinal wall. Pharmacokinetic study demonstrated that the area under the plasma concentration–time curve (AUC_0→∞) of paclitaxel in F127-PEI/TPGS/SPC/NaC micelles was much greater than that in TPGS/SPC/NaC micelles. This phenomenon deviated from the results of uptake studies by cells and permeability experiments through rat intestine and revealed that the micelle stability had a great effect on intestinal absorption of paclitaxel.     

Novel hydrogel microspheres of chitosan and pluronic F-127 for controlled release of 5-fluorouracil

Hydrogel microspheres of chitosan (CS) and Pluronic F127 (PF-127) were prepared by the emulsion-crosslinking method employing glutaraldehyde (GA) as a crosslinker. 5-Fluorouracil (5-FU), an anticancer drug with good water solubility, was encapsulated into hydrogel microspheres. Various formulations were prepared by varying the ratio of CS and PF-127, % drug loading and amount of GA. Microspheres were characterized by Fourier transform infrared (FTIR) spectroscopy to confirm the absence of chemical interactions between drug, polymer and the crosslinking agent. Scanning electron microscopy (SEM) was performed to study the surface morphology of the microspheres. SEM showed that microspheres have smooth shiny surfaces. Particle size, as measured by laser light scattering technique, gave an average size ranging from 110 to 382?µm. Differential scanning calorimetry (DSC) and X-ray diffraction (X-RD) studies were performed to understand the crystalline nature of the drug after encapsulation into hydrogel microspheres. Encapsulation of the drug up to 86% achieved was measured by UV spectroscopy. Equilibrium swelling experiments were performed in distilled water. Diffusion coefficients (D) of water through microspheres were estimated by an empirical equation. In vitro release studies indicated the dependence of release rate on the extent of crosslinking, drug loading and the amount of PF-127 used to produce the microspheres; slow release was extended up to 24?h. The release data were also fitted to an empirical equation to compute the diffusional exponent (n), which indicated that the release mechanism followed the non-Fickian trend.     

Programmable Drug Delivery from an Erodible Association Polymer System

An erodible association polymer system based on blends of cellulose acetate phthalate (CAP) and Pluronic F127, a block copolymer of poly(ethylene oxide) and poly(propylene oxide), has been investigated for its applicability to rate-programmed drug delivery. The compatibility and thermal properties were characterized by DSC and FTIR. Results from the thermal analysis indicate that the blends are compatible above 50% CAP, as revealed by a single composition-dependent glass transition temperature (T _g). The existence of molecular association through intermolecular hydrogen bonding between the carboxylic acid and the ether oxygen groups is supported by the observation of an upward shift in the IR carbonyl stretching frequency at increasing Pluronic F127 concentrations. Using theophylline as a model drug, the in vitro polymer erosion and drug release characteristics of the present polymer system were evaluated at different buffer pH's on a rotating-disk apparatus. The results show that the rates of both polymer erosion and drug release increase with the Pluronic F127 concentration in the blend. Further, at pH 4, the polymer erosion is minimal and the theophylline release appears to be governed mainly by diffusion through the polymer matrix. In contrast, at pH 7.4, the theophylline release is controlled primarily by the polymer surface erosion. To demonstrate the unique approach to programmed drug release based on the concept of non-uniform initial drug distribution, pulsatile patterns of drug release have been achieved successfully from the present surface-erodible polymer system using a multilaminate sample design with alternating drug-loaded layers. The results suggest that the pulsing frequency and peak rate of such pulsatile drug delivery are pH dependent; however, they can be modulated by varying the thickness, drug loading, and erosion rate of the constituent layers in the multilaminate.     

Development and characterization of morin hydrate-loaded micellar nanocarriers for the effective management of Alzheimer’s disease

The aim of this study was to prepare and characterise oral delivery of morin hydrate-loaded micellar nanocarriers using Pluronic P127 and Pluronic F123 for the effective management of Alzheimer’s disease. After administration of formulation brain and blood drug concentration were found to be highest for optimised morin hydrate-loaded micellar nanocarriers as compared to plain morin hydrate. Significant (p?3 induced Alzheimer’s disease in Wistar rats.     

两亲性嵌段共聚物普朗尼克的细胞毒性及细胞摄取

目的：考察不同型号、混合普朗尼克对MCF-7及耐药MCF-7的细胞毒性和细胞摄取,筛选出可供后续胶束研究的混合普朗尼克最优配比。方法：选取Pluronic F68、F127、P85、P105、P123,按HLB值分为2组,以一定比例交叉混合,采用CCK-8法和高效液相色谱法,测定普朗尼克、混合普朗尼克对MCF-7及耐药MCF-7的细胞毒性和细胞摄取量。结果：试验结果表明,F68、F127对细胞的毒性较小,而P85、P105、P123对细胞的毒性相对较大;当2种普朗尼克配比使用的质量浓度小于100 μg·mL^-1时,MCF-7及耐药MCF-7 2种细胞的存活率均大于70%。随着混合普朗尼克的浓度增加,细胞毒性均逐渐增强;F68与P85配比使用时,细胞毒性最大,且配比浓度为1：4时的细胞毒性大于1：2。Pluronic P85、P105、P123均可促进肿瘤细胞的药物摄取,Pluronic F68、F127基本不促进药物的摄取。F127-P123较其他混合普朗尼克表现出更强的摄取能力。结论：随着HLB值的降低及浓度的增大,普朗尼克对MCF-7及耐药MCF-7细胞的毒性增加。混合普朗尼克可以促进肿瘤细胞对于化疗药物的摄取。     

Adoption of polymeric micelles to enhance the oral bioavailability of dexibuprofen: formulation,in-vitro evaluation and in-vivo pharmacokinetic study in healthy human volunteers

Abstract

This work aimed to incorporate Dexibuprofen (DXI), the pharmacologically active and more potent form of ibuprofen, into polymeric micelles based tablets with enhanced oral bioavailability. Thin film hydration technique was employed to prepare DXI polymeric micelles using Pluronic® F127 and/or P123 solutions in different ratios (ranging from 1:1 up to 1:10). Prepared micelles were characterized regarding particle size, drug loading and entrapment efficiency. Selected formulae were lyophilized in presence of cryoprotectants and subjected to solid-state characterization as well as scanning and transmission electron microscopy. Subsequently, tablets were prepared and evaluated in-vitro regarding physical properties and drug release. An in-vivo pharmacokinetic study was performed in six healthy human volunteers in comparison to the commercially available tablet of DXI. Solid-state characterization proved that DXI was homogenously dispersed in Pluronic micelles’ matrices. Formula TF5 tablets comprising lyophilized micelles (F5; DXI: Pluronic F127 in 1:1 ratio and 0.25% mannitol) showed higher C_max and earlier t_max values than those of the commercial formula, where the relative bioavailability was calculated to be 160.15%. The experimental evidence in this research leads to the conclusion that polymeric micelles present enabling properties for oral delivery of drugs with low solubility.     

Adsorbed proteins influence the biological activity and molecular targeting of nanomaterials.

The possible combination of specific physicochemical properties operating at unique sites of action within cells and tissues has led to considerable uncertainty surrounding nanomaterial toxic potential. We have investigated the importance of proteins adsorbed onto the surface of two distinct classes of nanomaterials (single-walled carbon nanotubes [SWCNTs]; 10-nm amorphous silica) in guiding nanomaterial uptake or toxicity in the RAW 264.7 macrophage-like model. Albumin was identified as the major fetal bovine or human serum/plasma protein adsorbed onto SWCNTs, while a distinct protein adsorption profile was observed when plasma from the Nagase analbuminemic rat was used. Damaged or structurally altered albumin is rapidly cleared from systemic circulation by scavenger receptors. We observed that SWCNTs inhibited the induction of cyclooxygenase-2 (Cox-2) by lipopolysaccharide (LPS; 1 ng/ml, 6 h) and this anti-inflammatory response was inhibited by fucoidan (scavenger receptor antagonist). Fucoidan also reduced the uptake of fluorescent SWCNTs (Alexa647). Precoating SWCNTs with a nonionic surfactant (Pluronic F127) inhibited albumin adsorption and anti-inflammatory properties. Albumin-coated SWCNTs reduced LPS-mediated Cox-2 induction under serum-free conditions. SWCNTs did not reduce binding of LPS(Alexa488) to RAW 264.7 cells. The profile of proteins adsorbed onto amorphous silica particles (50-1000 nm) was qualitatively different, relative to SWCNTs, and precoating amorphous silica with Pluronic F127 dramatically reduced the adsorption of serum proteins and toxicity. Collectively, these observations suggest an important role for adsorbed proteins in modulating the uptake and toxicity of SWCNTs and nano-sized amorphous silica.