细胞体外暴露试验在吸入毒理学研究中的应用进展

吸入毒理学主要研究气体、蒸气和气溶胶等可吸入物质进入呼吸道后对生物体产生的不良反应。当前,由于对实验动物伦理和福利的倡导,体外替代方法受到越来越多的关注。吸入毒理学的体外替代方法常用细胞体外暴露试验,其中体外模型的构建以及毒性评估至关重要。而研究可吸入物质对呼吸道的不良反应需要模拟呼吸道细胞在体内生长的微环境,然后将细胞暴露于上述物质中,因此吸入毒理学对细胞模型及体外暴露装置提出了更高的要求。目前,体外细胞模型从原代细胞、细胞系扩大为共培养及商品化模型。针对细胞体外暴露试验现已开发多种气液界面暴露系统,并且可实现的暴露时间也已经进一步延长。本文针对呼吸道体外模型及应用、气液界面培养及暴露系统、试验检测指标等方面对近年来国内外细胞体外暴露试验应用于吸入毒理学的研究进展进行综述。     

Engineered carbon nanoparticles alter macrophage immune function and initiate airway hyper-responsiveness in the BALB/c mouse model

With the mass production of fullerenes currently underway, and the mass production of carbon nanotubes soon to follow, only a few studies have examined the biological consequences of manmade nanoparticle exposure in the mammalian system. This study examines carbon nanoparticle (CNP) exposure in both in vitro (murine BALB/c alveolar macrophages) and in vivo (murine BALB/c intranasal instillations) systems. Three types of CNP were examined (single-walled nanotubes, multi-walled nanotubes, and C₆₀ fullerenes). In vitro macrophage experiments included measurements of morphology changes, apoptosis, viability, and antigen-presenting cell function in response to CNP exposure. In vivo mouse experiments determined the inflammatory potential of CNP exposure in the lung using a BUXCO? apparatus along with cell differentials and cell morphology. This study presents evidence that CNP, accumulated in the plasma membranes of cells (disrupting lipid rafts), increased alveolar macrophage function with regard to antigen-presentation, significantly exacerbated airway hyper-responsiveness, and caused an influx of macrophages into the lung by posited mechanisms that involve the unique molecular and physical properties of CNP.     

Assessment of the drug loading,in vitro and in vivo release behavior of novel pH-sensitive hydrogel

Context: As a glucocorticoid drug, dexamethasone has good therapeutic effects for ulcerative colitis. pH-sensitive hydrogels could make conventional changes of volume in response with different pH values. Meanwhile, they could load drugs depending on its internal three-dimensional network structure.

Objective: Appropriate methods were used to improve the drug-loading capacity of hydrogel and exploring the colon-targeting character of dexamethasone hydrogel.

Materials and methods: Different solvents (ethanol and 1,2-propanediol) were employed to dissolve dexamethasone as well as hydrogel monomer materials (poly(ethylene glycol) methyl ether (MPEG)–poly(lactide acid)–acryloyl chloride macromonomer, itaconic acid (IA) and MPEG–methacrylate), then mixing them together to prepare hydrogel through the heat-initiated free radical polymerization method. Differential scanning calorimetry and X-ray diffraction methods were used to verify whether dexamethasone was loaded into hydrogels. In vitro drug release behavior and in vivo pharmacokinetic study were also investigated in detail.

Results: Dexamethasone was successfully loaded into hydrogel, and its loading capacity was improved (5?mg/g). Both the in vitro release study and the in vivo pharmacokinetic study showed the good colon-targeting character of the pH-sensitive P(LE–IA–MEG) hydrogel (T_max?=?1.0?h, C_max?=?2.16?µg/ml of dexamethasone; T_max?=?3.9?h, C_max?=?0.43?µg/ml of dexamethasone hydrogel).

Discussion: Dexamethasone could be targeted to the colon site by P(LE–IA–MEG) hydrogel, thereby improving its therapeutic effect and reduce its side effects.

Conclusion: P(LE–IA–MEG) hydrogel might have great potential application in colon-targeted drug delivery systems.     

A local drug delivery system based on visible light-cured glycol chitosan and doxorubicin⋅hydrochloride for thyroid cancer treatment in vitro and in vivo

Systemic drug delivery systems (SDDSs) for thyroid cancer treatment are associated with serious side effects including nausea, anorexia, and hair loss as a result of damage to normal tissues. In this study, we investigated the feasibility of a local DDS (LDDS) based on visible light-cured glycol chitosan (GC) hydrogel and doxorubicin?hydrochloride (DOX?HCl), called GC10/DOX, on thyroid cancer treatment in vivo. Visible light irradiation increased the storage modulus and swelling ratio of the GC10/DOX hydrogel precursor. The release of DOX?HCl from GC10/DOX exhibited two unique patterns comprising an initial burst within 18?hours, followed by a controlled and sustained release thereafter. In vitro cell viability testing showed that GC10/DOX had a greater antitumor effect than free DOX?HCl and GC10 hydrogel controls. In vivo, local injection of GC10/DOX near tumor tissue led to a superior antitumor effect compared with controls consisting of free DOX?HCl intravenously injected to the tail vein of thyroid cancer-bearing mouse and GC10 hydrogel subcutaneously injected near the tumor. Altogether, our results suggest that GC10/DOX may have clinical potential for thyroid cancer treatment.     

Hydrogel Containing Silica Shell Cross-Linked Micelles for Ocular Drug Delivery

Poly(2-hydroxyethyl methacrylate–methacrylic acid–ethylene glycol dimethacrylate) hydrogels loaded with silica shell cross-linked methoxy(polyethylene glycol)-block-polycaprolactone (MePEG-b-PCL) micelles with rod-like morphology were prepared as a potential soft contact lens material for the sustained release of ocular drugs. The silica shell cross-linked methoxy micelles (SSCMs) comprising a polycaprolactone core surrounded by a silica shell were synthesized and their size, morphology, stability, and drug release kinetics were evaluated. The relationships between the composition of the SSCM-loaded poly(2-hydroxyethyl methacrylate) (pHEMA)-based hydrogels and their transparency, surface wettability, and equilibrium water content were determined. Scanning electron microscopy (SEM) images of SSCM–hydrogel systems showed the presence of intact SSCMs within the hydrogel matrix. Dexamethasone acetate (DMSA), a hydrophobic ophthalmic drug, was loaded into the SSCMs prior to their incorporation into the hydrogels. In vitro release of DMSA from the SSCM–hydrogels, with varying drug loading levels, was observed for up to 30 days. Overall, the incorporation of rod-like SSCMs within pHEMA-based hydrogels provided sustained release over prolonged periods while maintaining optical transparency. This delivery system may be suitable for use as a therapeutic soft contact lens material.     

Effects of nickel-oxide nanoparticle pre-exposure dispersion status on bioactivity in the mouse lung

Nanotechnology is emerging as one of the world's most promising new technologies. From a toxicology perspective, nanoparticles possess two features that promote their bioactivity. The first involves physical–chemical characteristics of the nanoparticle, which include the surface area of the nanoparticle. The second feature is the ability of the nanoparticle to traverse cell membranes. These two important nanoparticle characteristics are greatly influenced by placing nanoparticles in liquid medium prior to animal exposure. Nanoparticles tend to agglomerate and clump in suspension, making it difficult to reproducibly deliver them for in vivo or in vitro experiments, possibly affecting experimental variability. Thus, we hypothesize that nanoparticle dispersion status will correlate with the in vivo bioactivity/toxicity of the particle. To test our hypothesis, nano-sized nickel oxide was suspended in four different dispersion media (phosphate-buffered saline (PBS), dispersion medium (DM), a combination of dipalmitoyl-phosphatidyl choline (DPPC) and albumin in concentrations that mimic diluted alveolar lining fluid), Survanta®, or pluronic (Pluronic F-68). Well-dispersed and poorly dispersed suspensions were generated in each media by varying sonication time on ice utilizing a Branson Sonifer 450 (25W continuous output, 20?min or 5?min, respectively). Mice (male, C57BL/6J, 7-weeks-old) were given 0–80?µg/mouse of nano-sized nickel oxide in the different states of dispersion via pharyngeal aspiration. At 1 and 7 d post-exposure, mice underwent whole lung lavage to assess pulmonary inflammation and injury as a function of dispersion status, dose and time. The results show that pre-exposure dispersion status correlates with pulmonary inflammation and injury. These results indicate that a greater degree of pre-exposure dispersion increases pulmonary inflammation and cytotoxicity, as well as decreases in the integrity of the blood–gas barrier in the lung.     

Injectable and biodegradable poly(organophosphazene) hydrogel as a delivery system of docetaxel for cancer treatment

Abstract

Although docetaxel (DTX) is an advanced taxoid, further augmentation of its properties is still required, such as improvement in its low aqueous solubility. Herein, we report the development of biodegradable/injectable poly(organophosphazene) (PPZ) hydrogels for the delivery of DTX without the use of organic solvents. An aqueous solution of PPZ containing α-amino-ω-methoxy-poly(ethylene glycol) (AMPEG) 750 instead of AMPEG 550 was prepared, thereby increasing the erosion capacity of the hydrogel by judicious balance of the hydrophobic/hydrophilic moieties. The safety of the hydrogel was demonstrated using a biocompatibility test. The PPZ aqueous solution (8?wt%) containing DTX exhibited a thermosensitive sol–gel–sol transition that was independent of the concentration of DTX (1–3?mg/mL). The in vitro release study indicated that the dominant release mechanism was either erosion or diffusion/erosion-controlled release depending on the DTX content of the hydrogel. The in vivo anticancer effect of the intratumorally injected PPZ system in human gastric cancer cell-xenografted mice was evaluated, which demonstrated a significantly (p?<?0.01) enhanced effect of the DTX-PPZ hydrogel system compared to the control (DTX solution, i.v.). In conclusion, the PPZ hydrogel may be a promising candidate for DTX delivery, affecting a decrease in the size of tumors with little toxicity prior to exeresis.     

Enhanced gene expression and reduced toxicity in mice using polyplexes of low-molecular-weight poly(ethylene imine) for pulmonary gene delivery

The aim of this study was to elicit improved gene expression and decreased cytotoxicity for pulmonary gene therapy by replacing the commonly used carrier 25?kDa branched poly(ethylene imine) (BPEI) by two PEI derivatives, low-molecular-weight PEI (LMWPEI) and polyethylene glycol?grafted PEI (PEGPEI). All polymers were shown to condense DNA to spherical particles of approximately 100?nm. Biocompatibility was investigated in vitro and in vivo. Although transfection was less efficient with LMWPEI-DNA in vitro, this polyplex caused the highest luciferase expression in the mouse lung after intratracheal instillation. While PEGPEI luciferase expression in vitro was approximately three times higher when compared to BPEI, a transfection rate at the level of naked DNA was observed in vivo. LMWPEI polyplexes were located in both the bronchial and alveolar cells, whereas BPEI polyplexes were mainly detected in bronchial cells. LMWPEI combines low cytotoxicity with high transfection efficiency in the mouse lung in vivo, rendering it a promising strategy for pulmonary gene delivery.     

Preparation and Characterization of PEG-albumin-curcumin Nanoparticles Intended to Treat Breast Cancer

The aim of present research was to prepare novel serum stable long circulating polymeric nanoparticles for curcumin with a modification to the well known and novel nanoparticle albumin bound technology. polyethylene glycol-albumin-curcumin nanoparticles were prepared using serum albumin and poly ethylene glycol using desolvation technique. Nanoparticles were characterized for encapsulation efficiency, particle size and surface morphology. Drug excipient compatibility was determined using fourier transform infrared spectroscopy. Physical state of the drug in the formulations was known by differential scanning colorimetry. In vitro release and solubility of the drug from nanoparticles were determined. In vivo Drug release, tissue uptake and kupffer cell uptake was determined with optimized nanoformulation in rats after intravenous administration. Cell viability assay was determined using breast cancer cell line MD-MB-231. Entrapment efficiency for prepared nanoparticle was above 95%. The polyethylene glycol-albumin-curcumin nanoparticles exhibited an interesting release profile with small initial burst followed by slower and controlled release. Solubility of the drug from the formulation was increased. A sustained release of drug from nanoparticles was observed for 35 days in both in vitro and in vivo studies with the optimized formulation. Polyethylene glycol-albumin-curcumin nanoparticles showed lesser liver and kupffer cell uptake as compared to that of curcumin-albumin nanoparticles suggesting the bestowment of stealthness to nanoparticles with pegylation. Also, the antiproliferative activity of polyethylene glycol-albumin-curcumin nanoparticle formulation was more as compared to native curcumin. Polyethylene glycol-albumin-curcumin nanoparticles thus developed can be conveniently used in breast cancer with improved efficacy compared to conventional therapies and as an alternate to nanoparticle albumin bound technology which is used in producing Abraxane, albumin based breast cancer targeting nanoparticles of paclitaxel.     

A novel micelle of coumarin derivative monoend-functionalized PEG for anti-tumor drug delivery: in vitro and in vivo study

In this paper, a novel micelle for anti-tumor drug delivery was reported. Two 7-carboxymethoxy coumarin molecules were immobilized on the terminal group of a methoxy poly(ethylene glycol) chain via l-lysine as linker. The amphiphilic 7-carboxymethoxy coumarin monoend-functionalized methoxy poly(ethylene glycol) (mPEG-Lys-DCOU) chains were self-assembled micelles. Anti-tumor drug doxorubicin was loaded in the mPEG-Lys-DCOU micelles and the release profile was studied. The cytotoxicity of mPEG-Lys-DCOU was evaluated by NIH 3T3 fibroblasts. The drug-loaded micelles were incubated with HepG2 tumor cells to investigate the in vitro anti-tumor effect. The in vivo inhibition efficacy of drug-loaded micelles was carried out on 4T1 breast cancer animal model. The results showed that both hydrophobic and π-π stacking interactions within mPEG-Lys-DCOU amphiphiles were contributed to the self-assembly. Both blank and drug loaded micelles were monodisperse nanoparticles with the average diameters around 300?nm. The release profile exhibited certain pH dependence. The drug release rate at pH?=?5.5 was much faster than that at pH?=?7.4. mPEG-Lys-DCOU amphiphiles were non-toxic to NIH 3T3 fibroblasts. Both in vitro and in vivo studies demonstrated that the inhibition efficacy of drug-loaded micelles were comparable to that of doxorubicin hydrochloride. mPEG-Lys-DCOU micelles are promising carriers for anti-tumor drug delivery.     

Cyclic RGD-poly(ethylene glycol)-polyethyleneimine is more suitable for glioblastoma targeting gene transfer in vivo

Arginine-glycine-aspartic acid (RGD) is a widely chosen ligand to improve the specific gene targeting transfection efficiency of polyethyleneimine (PEI) in vivo. However, the optimal RGD conjugating mode, RGD-poly(ethylene glycol)-PEI (RGD-PEG-PEI) or RGD-PEI-methoxyl poly(ethylene glycol) (RGD-PEI-mPEG) still remains controversial. In this study, RGD-PEG-PEI and RGD-PEI-mPEG were synthesized and compared with respects to their glioblastoma cell-binding capability and tumor-targeting ability of their complexes with plasmid DNA. These results demonstrated that RGD-PEG-PEI/plasmid enhanced green fluorescent protein (pEGFP)-N2 complexes had higher binding affinities with U87 cells than RGD-PEI-mPEG/pEGFP-N2 complexes. The gene transfection was also performed on U87 cells in vitro and in vivo. In vitro, both of the RGD-modified PEI derivatives enhanced the gene transfection efficiency to some extent. However, all of the complexes (with or without RGD modification) had high transfection efficiency. The biodistribution of RGD-PEG-PEI/pEGFP-N2 complexes in mice bearing subcutaneous glioblastomas were significantly greater than that of RGD-PEI-mPEG/pEGFP-N2 complexes, suggesting a more efficient gene transfection in vivo. In the RGD-PEG-PEI, the use of a PEG spacer was particularly important. These results indicated that RGD-PEG-PEI was more suitable for targeted gene transfer in vivo.     

Simple in vitro models can predict pulmonary toxicity of silver nanoparticles

To study the effects of nanomaterials after inhalation, a large number of in vitro lung models have been reported in literature. Although the in vitro models contribute to the reduction of animal studies, insufficient data exists to determine the predictive value of these in vitro models for the in vivo situation. The aim of this study was to determine the correlation between in vitro and in vivo data by comparing the dose metrics of silver nanoparticles in an in vitro lung model of increasing complexity to our previously published in vivo inhalation study. In vivo, the previously published study showed that the alveolar dose expressed as particle surface area is the most suitable dose metric to describe the toxicity of silver nanoparticles after inhalation. The results of the present study show that particle surface area is a suitable dose metric to describe the effects of silver nanoparticles when using a simple monolayer of lung epithelial cells. The dose metric shifted from particle surface area to particle mass when adding an increasing number of macrophages. In addition, a co-culture of endothelial cells, epithelial cells and macrophages on a Transwell® insert correlated less well to the in vivo results compared to the epithelial monolayer. We conclude that for studying the acute pulmonary toxicity of nanoparticles simple in vitro models using an epithelial monolayer better predict the in vivo response compared to complex co-culture models.     

Thermosensitive Injectable Hydrogel Enhances the Antitumor Effect of Embelin in Mouse Hepatocellular Carcinoma

Embelin, an active ingredient of traditional herbal medicine, is used to treat many diseases such as cancer. However, embelin is hydrophobic and insoluble in water, which makes it unsuitable for in vivo applications. In this study, we constructed an embelin-loaded thermosensitive injectable hydrogel system that we named Embelin/PECT^gel based on the amphiphilic triblock copolymer of poly (ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)–poly (ethylene glycol)–poly (ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT). The cytotoxicity and the antitumor effects of Embelin/PECT^gel on mouse hepatic cancers were investigated in vitro and in vivo. Results indicated that embelin was formulated in PECT hydrogel and could be continuously released from Embelin/PECT^gel, showing a higher cytotoxicity for H22 cells in vitro compared with free embelin. The aqueous solution of Embelin/PECT^gel transformed into gel at the injection site within seconds, which later eroded and degraded over time in vivo. A single local peritumoral injection of Embelin/PECT^gel in liver at a low dosage of 0.5 mg per mouse exhibited a significant antitumor effect, which was comparable to the antitumor effect of the embelin solution treatment at a total dose of 6 mg per mouse in mouse hepatic cancer. Embelin/PECT^gel, as a drug delivery system in liver, represents a novel therapeutic drug candidate for the clinical treatment of advanced hepatocellular carcinoma.     

Enhanced tumor targeting effects of a novel paclitaxel-loaded polymer: PEG–PCCL-modified magnetic iron oxide nanoparticles

Background: Multifunctional magnetic nanoparticles (MNP) have been newly developed for tumor-targeted drug carriers. To address challenges including biocompatibility, stability, nontoxicity, and targeting efficiency, here we report the novel drug deliverer poly(ethylene glycol) carboxyl–poly(?-caprolactone) modified MNP (PEG–PCCL-MNP) suitable for magnetic targeting based on our previous studies.

Methods: Their in vitro characterization and cytotoxicity assessments, in vivo cytotoxicity assessments, and antitumor efficacy study were elaborately investigated.

Results: The size of PEG–PCCL-MNP was 79.6?±?0.945?nm. PEG–PCCL-MNP showed little in vitro or in vivo cytotoxicity and good biocompatibility, as well as effective tumor-specific cell targeting for drug delivery with the presence of external magnetic field.

Discussion: PEG–PCCL-MNP is a potential candidate of biocompatible and tumor-specific targeting drug vehicle for hydrophobic drugs.     

In vitro and in vivo evaluation of thermosensitive chitosan hydrogel for sustained release of insulin

Injectable In situ gel-forming chitosan/β-glycerol phosphate (CS/β-Gp) solution can be introduced into the body in a minimally invasive manner prior to solidifying within the target tissue. This hydrogel is a good candidate for achieving a prolonged drug delivery system for insulin considering its high molecular weight. In addition to the physicochemical characterization of this hydrogel, in vitro and in vivo applications were studied as a sustained insulin delivery system. In the in vitro release studies, 19–63% of total insulin was released from the CS/β-Gp hydrogel within 150?h at different β-Gp and insulin concentrations. The best formulation was selected for in vivo experimentation to control the plasma glucose of diabetic mice models. The hypoglycemic effect of this formulation following subcutaneous injection in diabetic mice lasted 5?d, significantly longer than that of free insulin solution which lasted several hours.     

Recent advances in three-dimensional cell culturing to assess liver function and dysfunction: from a drug biotransformation and toxicity perspective

The liver is a vital organ fulfilling a central role in over 500 major metabolic functions, including serving as the most essential site for drug biotransformation. Dysfunction of the drug biotransformation processes may result in the exposure of the liver (and other organs) to hepatotoxins, potentially interacting with cellular constituents and causing toxicity and various lesions. Hepatotoxicity can be investigated on a tissue, cellular and molecular level by employing various in vivo and in vitro techniques, including novel three-dimensional (3?D) cell culturing methods. This paper reflects on the liver and its myriad of functions and the influence of drug biotransformation on liver dysfunction. Current in vivo and in vitro models used to study liver function and dysfunction is outlined, emphasizing their advantages and disadvantages. The advantages of novel in vitro 3?D cell culture models are discussed and the possibility of novel models to bridge the gap between in vitro and in vivo models is explained. Progression made in the field of cell culturing methods such as 3?D cell culturing techniques over the last decade promises to reduce the use of in vivo animal models in biotransformation and toxicological studies of the liver.     

Engineered nanoparticle exposure and cardiovascular effects: the role of a neuronal-regulated pathway

Abstract

Human and animal studies have confirmed that inhalation of particles from ambient air or occupational settings not only causes pathophysiological changes in the respiratory system, but causes cardiovascular effects as well. At an equal mass lung burden, nanoparticles are more potent in causing systemic microvascular dysfunction than fine particles of similar composition. Thus, accumulated evidence from animal studies has led to heightened concerns about the potential short- and long-term deleterious effects of inhalation of engineered nanoparticles on the cardiovascular system. This review highlights the new observations from animal studies, which document the adverse effects of pulmonary exposure to engineered nanoparticles on the cardiovascular system and elucidate the potential mechanisms involved in regulation of cardiovascular function, in particular, how the neuronal system plays a role and reacts to pulmonary nanoparticle exposure based on both in vivo and in vitro studies. In addition, this review also discusses the possible influence of altered autonomic nervous activity on preexisting cardiovascular conditions. Whether engineered nanoparticle exposure serves as a risk factor in the development of cardiovascular diseases warrants further investigation.     

Effect of Nanonization on Absorption of 301029: Ex Vivo and In Vivo Pharmacokinetic Correlations Determined by Liquid Chromatography/Mass Spectrometry

Purpose. To compare Caco-2 monolayer permeability and in vivo bioavailability of microparticle with nanoparticle 301029, a thiadiazole derivative, and to determine whether nanonization could improve oral bioavailability of the poorly soluble compound. Methods. The mean particle size of 301029 was reduced from 7 m to 280 nm by pearl milling. In the ex vivo assay, both microparticle and nanoparticle 301029 at the same concentration were separately added to apical side and were collected from basolateral side of Caco-2 monolayer. In the bioavailability study, the two particle sizes of 301029 were orally administered to rats, respectively, and blood samples were collected. Nanoparticle 301029 in culture medium and rat serum was detected by a liquid chomatography-mass spectrometer (LC/MS) coupled with atmospheric pressure chemical ionization (APCI). Results. Permeability rate and permeated amounts of nanoparticle 301029 across the Caco-2 monolayer were about four times higher than those of microparticle 301029. In a pharmacokinetic study, nanoparticle 301029 showed T_max about 1 h, whereas the microparticle 301029 showed T_max at 4 h. The C_max and AUC of nanoparticle 301029 were 3- to 4-fold greater than those of microparticle 301029, resulting in a significant increase in oral bioavailability of 301029 as compared with microparticle 301029. The ex vivo permeability and in vivo pharmacokinetic data indicate that nanoparticle formulation improves both absorption rate and absorption extent of the poorly soluble drug. Conclusions. Nanoparticle formulation enhances both Caco-2 monolayer permeability and rat oral bioavailability of the poorly soluble 301029. The result also demonstrates a close correlation between ex vivo Caco-2 permeability model and in vivo gastrointestinal absorption.     

Improving anti-tumor activity of sorafenib tosylate by lipid- and polymer-coated nanomatrix

In the present study, we select the Sylysia 350 (Sylysia) as mesoporous material, distearoylphosphatidylethanolamine-poly(ethylene glycol)₂₀₀₀ (DSPE-PEG) as absorption enhancer and hydroxy propyl methyl cellulose (HPMC) as crystallization inhibitor to prepare sorafenib tosylate (SFN) nanomitrix (MSNM@SFN) for improving the anti-tumor activity of SFN. The MSNM@SFN was prepared by solvent evaporation method. The solubility, dissolution, and bioavailability of SFN in MSNM@SFN were also investigated. The anti-tumor activity of MSNM@SFN was evaluated in vitro and in vivo. Our results indicated that the solubility and dissolution of SFN in MSNM@SFN were significantly increased. The oral bioavailability of SFN in MSNM@SFN was greatly improved 7.7-fold compared with that in SFN suspension. The enhanced anti-tumor activity of MSNM@SFN was confirmed in vitro and in vivo experiments. This nanomatrix developed in this study could be a promising drug delivery platform for improving the therapeutic efficacy of poorly water-soluble drugs.     

Cardiac-specific overexpression of metallothionein rescues nicotine-induced cardiac contractile dysfunction and interstitial fibrosis

Predictive toxicology aims at developing methodologies to relate the results obtained from in vitro experiments to in vivo exposure. In the case of polycyclic aromatic hydrocarbons (PAHs), a substantial amount of knowledge on effects and modes of action has been recently obtained from in vitro studies of gene expression. In the current study, we built a physiologically based toxicokinetic (PBTK) model to relate in vivo and in vitro gene expression in case of exposure to benzo(a)pyrene (BaP), a referent PAH. This model was calibrated with two toxicokinetic datasets obtained on rats exposed either through intratracheal instillation or through intravenous administration and on an in vitro degradation study. A good agreement was obtained between the model's predictions and the concentrations measured in target organs, such as liver and lungs. Our model was able to relate correctly the gene expression for two genes targeted by PAHs, measured in vitro on primary human macrophages and in vivo in rat macrophages after exposure to BaP. Combining in vitro studies and PBTK modeling is promising for PAH risk assessment, especially for mixtures which are more efficiently studied in vitro than in vivo.