RÉSUMÉ
Development of novel functional foods is trending as one of the hot topics in food science and food/beverage industries. In the present study, the anti-diabetic, anti-hyperlipidemic and histo-protective effects of the extra virgin olive oil (EVOO) enriched with the organosulfur diallyl sulfide (DAS) (DAS-rich EVOO) were evaluated in alloxan-induced diabetic mice. The ingestion of EVOO (500µL daily for two weeks) attenuated alloxan-induced elevated glucose, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), urea and creatinine. It also normalized the levels of triglycerides (TG), total cholesterols (TC), low-density lipoprotein-cholesterol (LDL-c) and their consequent atherogenic index of plasma (AIP) in diabetic animals. Additionally, EVOO prevented lipid peroxidation (MDA) and reduced the level of hydrogen peroxide (H2O2) in diabetic animals. Concomitantly, it enhanced the activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), reducing thereby tissue oxidative stress injury. The overall histologic (pancreas, liver, and kidney) alterations were also improved after EVOO ingestion. The manifest anti-diabetic, lipid-lowering and histo-protective properties of EVOO were markedly potentiated with DAS-rich EVOO suggesting possible synergistic interactions between DAS and EVOO lipophilic bioactive ingredients. Overall, EVOO and DAS-rich EVOO show promise as functional foods and/or adjuvants for the treatment of diabetes and its complications.
Sujet(s)
Composés allyliques , Diabète expérimental , Hypoglycémiants , Hypolipémiants , Huile d'olive , Sulfures , Animaux , Huile d'olive/composition chimique , Huile d'olive/pharmacologie , Diabète expérimental/traitement médicamenteux , Diabète expérimental/métabolisme , Composés allyliques/pharmacologie , Composés allyliques/usage thérapeutique , Sulfures/pharmacologie , Sulfures/usage thérapeutique , Sulfures/composition chimique , Hypoglycémiants/pharmacologie , Hypoglycémiants/usage thérapeutique , Souris , Hypolipémiants/pharmacologie , Mâle , Antioxydants/pharmacologie , Stress oxydatif/effets des médicaments et des substances chimiques , Peroxydation lipidique/effets des médicaments et des substances chimiques , Glycémie/métabolisme , Glycémie/effets des médicaments et des substances chimiques , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Foie/anatomopathologie , Pancréas/effets des médicaments et des substances chimiques , Pancréas/anatomopathologie , Pancréas/métabolisme , Glutathione peroxidase/métabolisme , Catalase/métabolisme , Peroxyde d'hydrogène/métabolisme , Superoxide dismutase/métabolisme , Rein/effets des médicaments et des substances chimiques , Rein/métabolisme , Rein/anatomopathologie , Alanine transaminase/sang , Alanine transaminase/métabolisme , Aspartate aminotransferases/métabolisme , Aspartate aminotransferases/sang , Triglycéride/sang , Triglycéride/métabolismeRÉSUMÉ
Colorectal cancer (CRC) is the third most common worldwide. Depending on its stage, chemotherapy is usually given after surgery when CRC has already metastasized to other organs like the liver or lungs. Unfortunately, the current antineoplastics used for CRC therapies involve toxicity and side effects due to their lack of site-specificity. To overcome the drawbacks of heavy chemotherapy, this study proposes to assess the efficacy of thymoquinone (TQ), a bioactive constituent of black seeds (Nigella sativa), as an antiproliferative and pro-apoptotic agent on an experimental CRC model in mice. TQ was encapsulated in lipid nanocapsules (LNCs), used as nanocarriers, in order to increase its specificity and cell absorption. TQ-loaded LNCs (TQ-LNCs) have a diameter of 58.3 ± 3.7 nm and 87.7 ± 4.5% TQ encapsulation efficiency. In turn, in vivo studies showed that the intratumoral administration of TQ-LNCs decreased the tumor size in colorectal cancer bearing mice compared to the control group. TQ-LNCs were more effective than free TQ for inducing tumor cell death. These results highlight the potential of TQ entrapped in LNCs as an anticancer agent for CRC treatment.
RÉSUMÉ
Voluntary drug intoxication is mainly due to drug overdose or the interaction of several drugs. Coma and its associated complications such as hypoventilation, aspiration pneumopathy, and heart rhythm disorders are the main hallmarks of drug intoxication. Conventional detoxification treatments, including gastric lavage or vomiting, administration of ipecac or activated charcoal (CH), and the use of antidotes, have proven to be inefficient and are generally associated with severe adverse effects. To overcome these limitations, titanate nanotubes (TiNTs) are proposed as an efficient emerging detoxifying agent because of their tubular shape and high adsorption capacity. In the present study, the detoxifying ability of TiNTs was evaluated on paracetamol (PR)-intoxicated rats. Results indicate that the loading ability of PR into TiNTs (70%) was significantly higher than that recorded for CH (38.6%). In simulated intestinal medium, TiNTs showed a controlled drug release of less than 10% after 72 h of incubation. In PR-intoxicated rats, TiNTs treatment resulted in a 64% decrease of PR after 4 h of poisoning versus 40% for CH. Concomitantly, TiNTs efficiently reduced PR absorption by 90% after 24 h of poisoning, attenuated the elevated levels of biochemical markers (i.e., alanine aminotransferase, aspartate aminotransferase, creatinine, and TNF-α) and mitigated oxidative stress by increasing the activity of superoxide dismutase and reducing the oxidized glutathione/total glutathione ratio, suggesting a histoprotective effect of TiNTs against paracetamol-induced toxicity in rats. In addition to their safety and high stability in the entire gastro-intestinal tract, biodistribution analysis revealed that TiNTs exhibited low intestinal absorption owing to their large cluster size of compact aggregate nanomaterials across the intestinal villi hindering the absorption of paracetamol. Collectively, these data provide a new and promising solution for in vivo detoxification. TiNTs are expected to have great potential for the treatment of voluntary and accidental intoxication in emergency care.
RÉSUMÉ
Ultrapure silicon nanoparticles (SiNPs) produced by femtosecond laser ablation in water have attracted great interest in the area of cancer therapy as they are efficient as photosensitizers in photodynamic therapy modality and can induce cell hyperthermia under radiofrequency radiation. Recently, we showed that these biocompatible nanoparticles were not able to reach tumors after intravenous injection in mice due to their rapid clearance from the bloodstream. In order to increase their half-life time and therefore their chances to reach and accumulate in tumors by an enhanced permeation retention (EPR) effect, a capping agent on SiNP surface acting as a colloidal stabilizer suspension is required. In this regard, this work focuses for the first time on the functionalization of SiNPs through the modification of their surface by chitosan (SiNPs-CH) in order to enhance their therapeutic properties in cancer therapy. Here, in vivo experiments were carried out during 15 days on nude mice developing a subcutaneously grafted malignant human brain tumor (glioblastoma). The characterization of SiNPs-CH showed an average hydrodynamic size of around 142 ± 65 nm as well as a relatively neutral charge (-5.2 mV) leading to a high colloidal suspension stability. The point of our work concerns the improvement of the biodistribution of SiNPs-CH with regard to tumors, the bloodstream, and organs. After the intravenous administration of 20 mg kg-1, all the studied parameters (animal behavior, organs' morphology, and histopathology) were in accord with the absence of toxicity due to SiNPs-CH, confirming their biocompatibility and even size and surface charge were modified compared to bare nanoparticles. Moreover an increased time in the bloodstream circulation of up to 7 days was observed, indicating the stealth of the nanoparticles, which could escape opsonization and premature elimination by macrophages and the reticuloendothelial system. As evidenced by silicon assessment, the interaction of the SiNPs-CH with the liver and spleen was significantly reduced compared to the bare nanoparticles. At the same time, SiNPs-CH were concentrated progressively in tumors from 12.03% after 1 day up to 39.55% after 7 days, confirming their uptake by the tumor microenvironment through the enhanced permeability retention effect. Subsequently, the silicon level declined progressively down to 33.6% after 15 days, evidencing the degradation of pH-sensitive SiNPs-CH under the acidic tumor microenvironment. Taken together, the stealthy SiNPs-CH exhibited an ideal biodistribution profile within the tumor microenvironment with a sustainable biodegradation and elimination profile, indicating their promising application in the nano-oncology field as a tumor-targeting system.
RÉSUMÉ
Flumequine (FLUM), a quinolone-derived antibiotic is one of the most prescribed drugs in aquaculture farms. However, its intensive use becomes worrisome because of its environmental risks and the emergence of FLUM-resistant bacteria. To overcome these problems we propose in this study the encapsulation and the delivery of FLUM by titanate nanotubes (TiNTs). Optimal FLUM loading was reached by suspending the dehydrated powder nanomaterials (FLUM : TiNTs ratio = 1 : 5) in ethanol. The drug entrapment efficiency was calculated to be 80% approximately with a sustained release in PBS at 37 °C up to 5 days. Then FLUM@TiNTs was evaluated for both its in vitro drug release and antimicrobial activity against Escherichia coli (E. coli). Spectacularly high antibacterial activity compared to those of free FLUM antibiotic was obtained confirming the efficiency of TiNTs to protect FLUM from rapid degradation and transformation within bacteria improving thereby its antibacterial effect. Indeed FLUM@TiNTs was efficient to decrease gradually the bacterial viability to reach ≈5% after 5 days versus ≈75% with free FLUM. Finally, the ex vivo permeation experiments on sea bass (Dicentrachus labrax) intestine shows that TiNTs act to increase the intestinal permeation of FLUM during the experiment. Indeed the encapsulated FLUM flux increased 12 fold (1.46 µg cm2 h-1) compared to the free antibiotic (0.18 µg cm2 h-1). Thanks to its physical properties (diameter 10 nm, tubular shape ) and its high stability in the simulated intestinal medium, TiNTs are easy internalized by enterocytes, thus involving an endocytosis mechanism, and then improve intestinal permeation of FLUM. Taken together, FLUM@TiNTs hold potential as an effective approach for enhancing the antimicrobial activity of FLUM and pave the way not only for future pharmacokinetic studies in the treatment and targeting of fish infections but also for instating of novel strategies that overcome the challenges associated with the abusive use of antibiotics in fish farming.
RÉSUMÉ
The present study delineates the effects of incorporation of 1% diallyl sulfide (DAS) into extra virgin olive oil (EVOO) on the physico-chemical characteristics, in vitro antioxidant, and in vivo hepatoprotective properties in CCl4-induced acute liver injury in mice. Results showed that the DAS-rich EVOO exhibited good oxidative stability over one-month storage and preserved its original quality-related parameters including major components (oleic acid, linoleic acid, and palmitic acid), and minor components (tocopherols, chlorophylls and carotenoids, tyrosol, hydroxytyrosol, elenolic acid, oleuropein and its aglycone, pinoresinol, vanilic acid, cinnamic acid, ferulic acid, luteolin, apigenin, and sterols). Compared with EVOO or DAS, the DAS-rich EVOO displayed the highest DPPH and ABTS-radical scavenging activities and showed the strongest cellular antioxidant activity (CAA). In connection with its free radical scavenging activity and CAA, DAS-rich EVOO significantly normalized the serum ALT and AST levels and prevented the increase in interleukin-6 in CCl4-intoxicated mice. The manifest anti-inflammatory and hepatoprotective effects of DAS-rich EVOO were further supported by liver histopathological examinations. Overall, the EVOO enrichment with DAS could open up opportunities for the development of novel functional food with improved antioxidant and hepatoprotective properties.
RÉSUMÉ
Titanate nanotubes (TiNTs) produced by the static hydrothermal process present a promising nanosystem for nanomedicine. However, the behavior of these nanotubes in vivo is not yet clarified. In this work, for the first time, we investigated the toxicity of these materials, their pharmacokinetic profile, and their biodistribution in mice. A high dose of TiNTs (45 mg/kg) was intravenously injected in mice and monitored from 6 h to 45 days. The histological examination of organs and the analysis of liver and kidney function markers and then the inflammatory response were in agreement with a long-term innocuity of these nanomaterials. The parameters of pharmacokinetics revealed the rapid clarification of TiNTs from the bloodstream after 6 h of the intravenous injection which then mainly accumulated in the liver and spleen, and their degradation and clearance in these tissues were relatively slow (>4 weeks). Interestingly, an important property of these materials is their slow dissolution under the lysosome acid environment, rendering them biodegradable. It is noteworthy that TiNTs were directly eliminated in urine and bile ducts without obvious toxicity in mice. Altogether, all these typical in vivo tests studying the TiNT pharmacokinetics, toxicity, and biodistribution are supporting the use of these biocompatible nanomaterials in the biomedical field, especially as a nanocarrier-based drug delivery system.
RÉSUMÉ
In the present study, the omega-3-rich oil from fish viscera and gill by-products, and caffeoylquinic-rich powder of artichoke bract by-products were used for the enrichment of wheat flour chips. Incorporation of these ingredients improved the lipid profile by increasing the level of polyunsaturated essential fatty acids mainly linoleic, linolenic, eicosapentaenoic, and docosahexaenoic acids enhancing thereby their nutritional quality. In alloxan-induced diabetic mice, the novel products reverts the blood glucose and serum markers including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea, and creatinine to their normal levels. Concomitantly, they prevented lipid peroxidation and activated antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). They ameliorate the lipid profile by reducing triglycerides, cholesterol, and LDL. Additional efforts aimed at investigating the potential of other raw materials including algal biomass, and shrimps as a sustainable source of valuable ingredients would contribute to the development of new products with improved nutritional and functional attributes. PRACTICAL APPLICATIONS: Icorporation of cheap, available, and functional ingredients from fish (omega-3-rich oil) and artichoke bract by-products into wheat flour chips could be successfully adopted for the development of functional foods destined for diabetic patient.
Sujet(s)
Cynara scolymus , Diabète expérimental , Acides gras omega-3 , Animaux , Antioxydants , Diabète expérimental/traitement médicamenteux , Farine , Humains , Hypoglycémiants/usage thérapeutique , Hypolipémiants , Souris , Poudres , TriticumRÉSUMÉ
Artichoke floral stems (AFS) food waste by-products were examined for their phytochemical constituents and their in vitro and in vivo biological activities. Although that the highest total phenol content and total flavonoid content were found in ethyl acetate extract, methanol extract possessed the strongest DPPH and ABTS radical scavenging activity, and showed the highest reducing ferric antioxidant power (FRAP). The anti-acetylcholinesterase activity was higher in butanol extract, whereas the ethyl acetate extract had the highest inhibitory effect on heat-induced protein denaturation. In alloxan-induced diabetic mice, the AFS methanol extract (AFSE) rich in caffeoylquinic acids and flavones reduced blood glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, creatinine, and improved liver, and renal antioxidative status. Administration of AFSE to diabetic mice reduced total cholesterol, triglycerides, LDL-cholesterol, and the atherogenic index of plasma (AIP) suggesting its hypolipidemic action. Overall, AFS could be considered as attractive source of health-promoting ingredients.
Sujet(s)
Cynara scolymus/composition chimique , Composés phytochimiques/analyse , Extraits de plantes/composition chimique , Alanine transaminase , Animaux , Antioxydants/composition chimique , Antioxydants/métabolisme , Bactéries/effets des médicaments et des substances chimiques , Glycémie/analyse , Candida albicans/effets des médicaments et des substances chimiques , Chromatographie en phase liquide à haute performance , Cynara scolymus/métabolisme , Diabète expérimental/induit chimiquement , Diabète expérimental/traitement médicamenteux , Diabète expérimental/anatomopathologie , Flavonoïdes/analyse , Fleurs/composition chimique , Fleurs/métabolisme , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Mâle , Souris , Tests de sensibilité microbienne , Phénols/analyse , Composés phytochimiques/composition chimique , Composés phytochimiques/pharmacologie , Composés phytochimiques/usage thérapeutique , Extraits de plantes/pharmacologie , Tiges de plante/composition chimique , Tiges de plante/métabolisme , Spectrométrie de masse ESIRÉSUMÉ
Poisoning and accidental oral intoxication are major health problems worldwide. Considering the insufficient efficacy of the currently available detoxification treatments, a pioneering oral detoxifying adsorbent agent based on a single biocompatible metal-organic framework (MOF) is here proposed for the efficient decontamination of drugs commonly implicated in accidental or voluntary poisoning. Furthermore, the in vivo toxicity and biodistribution of a MOF via oral administration have been investigated for the first time. Orally administered upon a salicylate overdose, this MOF is able to reduce the salicylate gastrointestinal absorption and toxicity more than 40-fold (avoiding histological damage) while exhibiting exceptional gastrointestinal stability (<9% degradation), poor intestinal permeation, and safety.
Sujet(s)
Antidotes/usage thérapeutique , Acide acétylsalicylique/intoxication , Mauvais usage des médicaments prescrits/prévention et contrôle , Réseaux organométalliques/usage thérapeutique , Administration par voie orale , Adsorption , Animaux , Antidotes/administration et posologie , Antidotes/métabolisme , Antidotes/toxicité , Acide acétylsalicylique/sang , Acide acétylsalicylique/composition chimique , Acide acétylsalicylique/urine , Femelle , Absorption gastro-intestinale/effets des médicaments et des substances chimiques , Jéjunum/anatomopathologie , Foie/anatomopathologie , Réseaux organométalliques/administration et posologie , Réseaux organométalliques/métabolisme , Réseaux organométalliques/toxicité , Rat Wistar , Estomac/anatomopathologie , Distribution tissulaireRÉSUMÉ
This study was aimed at investigating the chemical composition (proximate, minerals, fatty acids and phenolic compounds) and the in vitro (antimicrobial, radical scavenging, anti-acetylcholinesterase and protein denaturing activities) and in vivo (anti-diabetic and histo-protective effects in alloxan-induced diabetic mice) biological activities of broad bean pods (BBPs), a food waste by-product material. The results showed that BBPs have high dietary fiber (57.46%), carbohydrate (18.93%) and protein (13.81%) content versus low fat content (<1%) contributing to a low energy value of 139.24 kcal per 100 g. Profiling of fatty acids showed an abundance of the essential polyunsaturated α-linolenic and linoleic acids, exhibiting an excellent nutritional quality as revealed by their low atherogenic and thrombogenic indices and their hypocholesterolemic properties. The methanol extract which exhibited the highest total phenolic, flavonoid and tannin contents was found to be the most active extract in terms of antimicrobial and anti-radical activities. In alloxan-induced diabetic mice, the oral administration of a methanol extract (500 mg per kg bw) attenuated the elevated levels of serum alanine aminotransferase (ALA), aspartate aminotransferase (AST), and alkaline phosphatase activities, and urea, uric acid, and creatinine. It effectively normalized the status of lipid profiles, mitigated oxidative stress through the activation of antioxidant enzymes (CAT, GPx and SOD), and alleviated oxidative stress-mediated histopathological changes in the pancreas, liver, kidney and testis. Compositional analysis by HPLC-PDA-ESI-MS/MS revealed the presence of flavan-3-ols (catechin, epicatechin and their derivatives), flavones (apigenin derivatives) and flavonols (glycosides of quercetin and kaempferol), among others. These findings suggest that BBPs may be an effective functional food for the management of diabetes and its complications.
Sujet(s)
Diabète expérimental/diétothérapie , Compléments alimentaires , Fruit/composition chimique , Hypoglycémiants/usage thérapeutique , Déchets industriels/analyse , Extraits de plantes/usage thérapeutique , Vicia faba/composition chimique , Animaux , Antibactériens/composition chimique , Antibactériens/économie , Antibactériens/isolement et purification , Antibactériens/usage thérapeutique , Antioxydants/composition chimique , Antioxydants/économie , Antioxydants/isolement et purification , Antioxydants/usage thérapeutique , Marqueurs biologiques/sang , Diabète expérimental/sang , Diabète expérimental/anatomopathologie , Compléments alimentaires/analyse , Tests d'agents antimicrobiens par diffusion à partir de disques , Industrie de la transformation des aliments/économie , Fruit/économie , Fruit/croissance et développement , Humains , Hypoglycémiants/composition chimique , Hypoglycémiants/économie , Hypoglycémiants/isolement et purification , Déchets industriels/économie , Mâle , Méthanol/composition chimique , Souris , Valeur nutritive , Stress oxydatif , Extraits de plantes/composition chimique , Extraits de plantes/économie , Extraits de plantes/isolement et purification , Répartition aléatoire , Solvants/composition chimique , Tunisie , Vicia faba/croissance et développementRÉSUMÉ
Si/SiOx nanoparticles (NPs) produced by laser ablation in deionized water or aqueous biocompatible solutions present a novel extremely promising object for biomedical applications, but the interaction of these NPs with biological systems has not yet been systematically examined. Here, we present the first comprehensive study of biodistribution, biodegradability and toxicity of laser-synthesized Si-SiOx nanoparticles using a small animal model. Despite a relatively high dose of Si-NPs (20 mg/kg) administered intravenously in mice, all controlled parameters (serum, enzymatic, histological etc.) were found to be within safe limits 3 h, 24 h, 48 h and 7 days after the administration. We also determined that the nanoparticles are rapidly sequestered by the liver and spleen, then further biodegraded and directly eliminated in urine without any toxicity effects. Finally, we found that intracellular accumulation of Si-NPs does not induce any oxidative stress damage. Our results evidence a huge potential in using these safe and biodegradable NPs in biomedical applications, in particular as vectors, contrast agents and sensitizers in cancer therapy and diagnostics (theranostics).
Sujet(s)
Biodisponibilité , Lasers , Nanostructures/administration et posologie , Silicium/administration et posologie , Silicium/pharmacocinétique , Oligoéléments/administration et posologie , Oligoéléments/pharmacocinétique , Administration par voie intraveineuse , Animaux , Foie/composition chimique , Souris , Nanomédecine/méthodes , Nanostructures/effets indésirables , Silicium/effets indésirables , Rate/composition chimique , Oligoéléments/effets indésirables , Urine/composition chimiqueRÉSUMÉ
We employ a method of femtosecond laser fragmentation of preliminarily prepared water-dispersed microcolloids to fabricate aqueous solutions of ultrapure bare Si-based nanoparticles (Si-NPs) and assess their potential for biomedical applications. The nanoparticles appear spherical in shape, with low size dispersion and a controllable mean size, from a few nm to several tens of nm, while a negative surface charge (-35 mV ± 0.10 according to z-potential data) provides good electrostatic stabilization of colloidal Si-NP solutions. Structural analysis shows that the Si-NPs are composed of Si nanocrystals with inclusions of silicon oxide species, covered by a SiOx (1 < x < 2) shell, while the total oxide content depends on whether the fragmentation is performed in normal oxygen-saturated water (oxygen-rich conditions) or in water deoxygenated by pumping with noble gases (Ag or He) before and during the experiment (oxygen-free conditions). Our dissolution tests show the excellent water-solubility of all the NPs, while more oxidized NPs demonstrate much faster dissolution kinetics, which is explained by oxidation-induced defects in the core of the Si-NPs. Finally, by examining the interaction of the NPs with human cells after 72 h of incubation at different concentrations, we report the absence of any adverse effects of the NPs up to high concentrations (50 µg mL-1) and a good internalization of NPs via a classical endocytosis mechanism. Possessing far superior purity compared to their chemically synthesized counterparts and enabling a variety of imaging and therapeutic functionalities, the laser-synthesized Si-NPs are promising for safe and efficient applications in nanomedicine.
RÉSUMÉ
The quantification of paclitaxel, a chemotherapy drug used to treat different types of cancers, has been performed from complete cell culture medium and cell lysate samples using a simple liquid-liquid extraction procedure in conjunction with liquid chromatography tandem mass spectrometry (LC-MS/MS). A simple sample preparation using methanol and acetic acid as a weaker acid was applied to avoid paclitaxel destruction and to achieve recovery exceeding 80 % from both matrices spiked with paclitaxel and docetaxel used as internal standard. This rapid, simple, selective and sensitive method enabled the quantification of paclitaxel within the linear range of 1-250nM in culture medium and 5-250nM in cell lysate. The lower limit of quantification was achieved in cell culture medium and cell lysates at 0.2 and 1pmol, respectively. This method was successfully applied to human non-small cell lung carcinoma cells (A549 cells) in order to quantify the amount of paclitaxel in both cell culture medium and lysate after incubation with 5, 50 and 100nM of paclitaxel. This ultra-sensitive method promises the quantification of ultra-low concentrations of paclitaxel released from any nanocarriers, allowing the determination of the kinetic profile of drug release, which is an essential parameter to validate the use of nanocarriers for drug delivery in cancer therapy.
Sujet(s)
Antinéoplasiques d'origine végétale/analyse , Chromatographie en phase liquide à haute performance/méthodes , Vecteurs de médicaments/composition chimique , Extraction liquide-liquide/méthodes , Nanoparticules/composition chimique , Paclitaxel/analyse , Spectrométrie de masse en tandem/méthodes , Calibrage , Techniques de culture cellulaire , Lignée cellulaire tumorale , Milieux de culture/composition chimique , Libération de médicament , Humains , Limite de détection , Reproductibilité des résultatsRÉSUMÉ
Nanoscale mesoporous iron carboxylates metal-organic frameworks (nanoMOFs) have recently emerged as promising platforms for drug delivery, showing biodegradability, biocompatibility and important loading capability of challenging highly water-soluble drugs such as azidothymidine tryphosphate (AZT-TP). In this study, nanoMOFs made of iron trimesate (MIL-100) were able to act as efficient molecular sponges, quickly adsorbing up to 24 wt% AZT-TP with entrapment efficiencies close to 100%, without perturbation of the supramolecular crystalline organization. These data are in agreement with molecular modelling predictions, indicating maximal loadings of 33 wt% and preferential location of the drug in the large cages. Spectrophotometry, isothermal titration calorimetry, and solid state NMR investigations enable to gain insight on the mechanism of interaction of AZT and AZT-TP with the nanoMOFs, pointing out the crucial role of phosphates strongly coordinating with the unsaturated iron(III) sites. Finally, contrarily to the free AZT-TP, the loaded nanoparticles efficiently penetrate and release their cargo of active triphosphorylated AZT inside major HIV target cells, efficiently protecting against HIV infection.
Sujet(s)
Antirétroviraux/administration et posologie , Antirétroviraux/composition chimique , Composés du fer III/administration et posologie , Composés du fer III/composition chimique , Nanocomposites/composition chimique , Antirétroviraux/pharmacocinétique , Cellules cultivées , Didésoxynucléotides/administration et posologie , Didésoxynucléotides/composition chimique , Didésoxynucléotides/pharmacocinétique , Composés du fer III/pharmacocinétique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Humains , Agranulocytes/métabolisme , Agranulocytes/virologie , Nanocomposites/administration et posologie , Nucléotides thymidyliques/administration et posologie , Nucléotides thymidyliques/composition chimique , Nucléotides thymidyliques/pharmacocinétique , Zidovudine/administration et posologie , Zidovudine/analogues et dérivés , Zidovudine/composition chimique , Zidovudine/pharmacocinétiqueRÉSUMÉ
INTRODUCTION: CYP3A4 is one of the most important of all drug-metabolizing enzymes. Although several direct or indirect quantification methods have been proposed for the determination of the CYP3A4 activity, the sample preparation is mostly tedious and usually requires time consuming separate extraction steps and solid-phase extraction. METHODS: Here, we developed a simple and selective HPLC method, coupled to photodiode array detection for direct determination of CYP3A4-mediated testosterone hydroxylase activity in hepatic microsomes of rats. After microsome incubation, a single-step liquid-phase extraction of specific substrates, testosterone and its metabolite 6-hydroxytestosterone, together with the salicylamid acid used as an internal standard, was applied. The analytical method was fully validated by the determination of different parameters (intra- and inter-day variability of 6-ß-OH-testosterone concentration, accuracy and limit of detection). Finally, this method was applied to quantify the CYP3A4 activity of rats intravenously administered with either the mesoporous iron(III) trimesate MIL-100 nanocarrier (MIL stands for Materials from Institut Lavoisier) or with its corresponding organic linker. RESULTS: All analytes were simultaneously separated from a single run shorter than 10 min, reaching relative standard deviations of intra- and inter-day precision <18.5% and an accuracy of estimated 6-ß-OH-testosterone concentrations ranging from 95 to 111%. The mean±standard deviation absolute recoveries of 6-ß-OH-testosterone at 0.01, 1.00 and 20.00 µg/mL were 97±4%, 101±3% and 99±2%, respectively while it reached 98±3% for the internal standard. DISCUSSION: The developed HPLC-PDA method enables the accurate and sensitive determination of the CYP3A4 activity through the quantification of the 6-ß-OH-testosterone produced by the CYP3A4-mediated testosterone hydroxylase in rat hepatic microsomal suspensions. Additionally, the rapid procedure offers an economical advantage with respect to resources and operator time. Finally, the determination of CYP3A4 activity in hepatic microsomes of rats administered with nanoparticles of the porous iron(III) trimesate nanocarrier shows no significant differences between control, trimesic and nanoparticle groups, evidencing that the linker is not metabolized by CYP3A4.
Sujet(s)
Cytochrome P-450 enzyme system/métabolisme , Extraction liquide-liquide/méthodes , Microsomes du foie/enzymologie , Spectrophotométrie UV/méthodes , Animaux , Chromatographie en phase liquide à haute performance/méthodes , Cytochrome P-450 CYP3A , Femelle , Tests de criblage à haut débit , Hydroxytestostérone/analyse , Hydroxytestostérone/métabolisme , Limite de détection , Rats , Rat Wistar , Reproductibilité des résultatsRÉSUMÉ
Tetramethyl-terephthalate (TMT) is the constitutive linker of the flexible porous iron(III) carboxylate Metal Organic Framework (MOF) MIL-88B_4CH3 based drug nanocarrier (MIL stands for Material from Institut Lavoisier). A method for the determination of the concentration of tetramethyl-terephthalic acid has been developed in different biological rat matrices (liver, spleen and urine) using a liquid-liquid phase extraction and high-performance liquid chromatography (HPLC) coupled to photodiode array detection with 4-aminosalicylic acid as internal standard. The extraction conditions of TMT have been varied from urine to tissue depending on the complexity of the biological matrices. The chromatographic separation was performed with a gradient elution. In all matrices, the limits of detection and quantification of TMT was 0.01 and 0.05 µg ml⻹, respectively. The recovery of the TMT reached 86, 89 and 97% for urine, spleen and liver tissues, respectively. The linearity of the calibration curves in urine and tissues was satisfactory in all cases as evidenced by correlation coefficients >0.990. The within-day and between-day precisions were <15% (n=6) and the accuracy ranged in all cases between 86 and 103%. This method has finally allowed the quantification of TMT in rat urine and in tissue samples of rats administered intravenously with iron(III) tetramethyltherepthalate MIL-88B_4CH3 nanoparticles.
Sujet(s)
Chromatographie en phase liquide à haute performance/méthodes , Extraction liquide-liquide/méthodes , Foie/métabolisme , Acides phtaliques/métabolisme , Rate/métabolisme , Animaux , Limite de détection , Rats , Reproductibilité des résultats , Spectrophotométrie UVRÉSUMÉ
Countless studies showed that [60]fullerene (C(60)) and derivatives could have many potential biomedical applications. However, while several independent research groups showed that C(60) has no acute or sub-acute toxicity in various experimental models, more than 25 years after its discovery the in vivo fate and the chronic effects of this fullerene remain unknown. If the potential of C(60) and derivatives in the biomedical field have to be fulfilled these issues must be addressed. Here we show that oral administration of C(60) dissolved in olive oil (0.8 mg/ml) at reiterated doses (1.7 mg/kg of body weight) to rats not only does not entail chronic toxicity but it almost doubles their lifespan. The effects of C(60)-olive oil solutions in an experimental model of CCl(4) intoxication in rat strongly suggest that the effect on lifespan is mainly due to the attenuation of age-associated increases in oxidative stress. Pharmacokinetic studies show that dissolved C(60) is absorbed by the gastro-intestinal tract and eliminated in a few tens of hours. These results of importance in the fields of medicine and toxicology should open the way for the many possible -and waited for- biomedical applications of C(60) including cancer therapy, neurodegenerative disorders, and ageing.
Sujet(s)
Fullerènes/pharmacologie , Huiles végétales/composition chimique , Administration par voie orale , Vieillissement/effets des médicaments et des substances chimiques , Animaux , Fullerènes/administration et posologie , Fullerènes/composition chimique , Fullerènes/pharmacocinétique , Mâle , Huile d'olive , Stress oxydatif/effets des médicaments et des substances chimiques , Rats , Rat WistarSujet(s)
Vecteurs de médicaments , Médecine , Composés organométalliques , Animaux , Vecteurs de médicaments/administration et posologie , Vecteurs de médicaments/composition chimique , Vecteurs de médicaments/métabolisme , Systèmes de délivrance de médicaments , Gaz/composition chimique , Gaz/métabolisme , Humains , Composés organométalliques/administration et posologie , Composés organométalliques/composition chimique , Composés organométalliques/métabolismeRÉSUMÉ
Quantification of fumaric acid, an endogenous dicarboxylic acid with interesting biomedical applications either through its own biological activity or as a linker constitutive of the porous iron(III) fumarate metal organic framework (MOF) MIL-88A based drug nanocarrier (MIL stands for Material from Institut Lavoisier), has been developed in different rat biological complex media (liver, spleen and urine). After a liquid-liquid extraction procedure, fumaric acid concentration was determined by a simple and accurate high-performance liquid chromatography (HPLC) method coupled to a photodiode-array detector (PDA) using aminosalicylic acid as internal standard (IS) and a gradient elution. The recovery of fumaric acid reaches 89% and 92% for urine (for concentrations of 0.05 and 1µgml(-1), respectively) and 90% for liver and spleen tissues, exceeding 89% in all instances in comparison with the IS. Linearity has been kept from 0.05 to 1µgml(-1) and from 0.5 to 10µgg(-1) of fumaric acid in urine and tissues, respectively. The limit of detection of the method was 0.01µg per injection. This method has finally allowed the quantification of fumaric acid in rat urine and tissue samples after the intravenous administration of MIL-88A nanoparticles.