Zinberg's Interaction Model implies that the content of a drug-induced experience is a function of the pharmacological properties of the drug, the set (the user’s characteristics e.g. motivation and personality), and the setting (the physical and social context). The current research investigated the function of the set and setting and their role in shaping the psychological effects of 3,4-methylenedioxmethamphetamine (MDMA), as well as their role in reducing the risk of drug abuse. An online survey was distributed among adult MDMA polydrug users (n = 158) and MDMA-naïve controls (alcohol, nicotine and cannabis users, n = 138). Participants answered questions regarding their pattern of drug use, their motivation for MDMA use and the setting (e.g. clubbing, home with friends), as well as the subjective effects of MDMA. Participants also completed a range of self-report measures of self-reflection and insight, emotional intelligence, and personality, as well as a drug dependency measure. MDMA users displayed higher levels of self-reflection and insight, openness to new experience and lower levels of neuroticism and conscientiousness, in comparison to the control group. The significant predictors of self-reflection and insight were openness, emotional intelligence, MDMA use, extraversion and neuroticism. When the analysis was rerun only for the MDMA group, the significant predictors of self-reflection and insight were openness, emotional intelligence and self-insight effects of MDMA. High levels of self-reported negative effects of MDMA were predictors of a problematic drug use. These findings suggest that there might be a relationship between MDMA use and higher levels of self-reflection and insight; however, longitudinal studies are required to further investigate the causality of this relationship. The results add to existing evidence that MDMA has potential for altering emotional experiences. Further research utilising a prospective design is warranted.

New psychoactive substances (NPSs) have appeared on the recreational drug market at an unprecedented rate in recent years. Many are not new drugs but failed products of the pharmaceutical industry. The speed and variety of drugs entering the market poses a new complex challenge for the forensic toxicology community. The detection of these substances in biological matrices can be difficult as the exact compounds of interest may not be known. Many NPS are sold under the same brand name and therefore users themselves may not know what substances they have ingested. The majority of analytical methods for the detection of NPSs tend to focus on a specific class of compounds rather than a wide variety. In response to this, a robust and sensitive method was developed for the analysis of various NPS by solid phase extraction (SPE) with gas chromatography mass spectrometry (GCMS). Sample preparation and derivatisation were optimised testing a range of SPE cartridges and derivatising agents, as well as derivatisation incubation time and temperature. The final gas chromatography mass spectrometry method was validated in accordance with SWGTOX 2013 guidelines over a wide concentration range for both blood and urine for 23 and 25 analytes respectively. This included the validation of 8 NBOMe compounds in blood and 10 NBOMe compounds in urine. This GC-MS method was then applied to 8 authentic samples with concentrations compared to those originally identified by NMS laboratories. The rapid influx of NPSs has resulted in the re-analysis of samples and thus, the stability of these substances is crucial information. The stability of mephedrone was investigated, examining the effect that storage temperatures and preservatives had on analyte stability daily for 1 week and then weekly for 10 weeks. Several laboratories identified NPSs use through the cross-reactivity of these substances with existing screening protocols such as ELISA. The application of Immunalysis ketamine, methamphetamine and amphetamine ELISA kits for the detection of NPS was evaluated. The aim of this work was to determine if any cross-reactivity from NPS substances was observed, and to determine whether these existing kits would identify NPS use within biological samples. The cross- reactivity of methoxetamine, 3-MeO-PCE and 3-MeO-PCP for different commercially point of care test (POCT) was also assessed for urine. One of the newest groups of compounds to appear on the NPS market is the NBOMe series. These drugs pose a serious threat to public health due to their high potency, with fatalities already reported in the literature. These compounds are falsely marketed as LSD which increases the chance of adverse effects due to the potency differences between these 2 substances. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was validated in accordance with SWGTOX 2013 guidelines for the detection for 25B, 25C and 25I-NBOMe in urine and hair. Long-Evans rats were administered 25B-, 25C- and 25I-NBOMe at doses ranging from 30-300 µg/kg over a period of 10 days. Tail flick tests were then carried out on the rats in order to determine whether any analgesic effects were observed as a result of dosing. Rats were also shaved prior to their first dose and reshaved after the 10-day period. Hair was separated by colour (black and white) and analysed using the validated LC-MS/MS method, assessing the impact hair colour has on the incorporation of these drugs. Urine was collected from the rats, analysed using the validated LC-MS/MS method and screened for potential metabolites using both LC-MS/MS and quadrupole time of flight (QToF) instrumentation.

The process of in vitro-in vivo extrapolation (IVIVE) can be used to predict pharmacokinetics of drugs in patients using data from in vitro systems. This process relies on the use of experimentally obtained scaling factors, such as abundances of different drug-metabolising enzymes and microsomal protein content (MPPGL). The use of simulators is dependent on abundances and activities of pharmacokinetically relevant enzymes. The incorporation of inter-individual variability in abundances of enzymes, correlations between enzyme expression patterns, and relationships between genetic, physiological, and environmental factors and enzyme expression and activity can make predictions using IVIVE and simulations of pharmacokinetic experiments in virtual populations more accurate and realistic. Incorporation of variability and correlations can also assist in predicting extreme cases where drug therapy may be ineffective or may cause adverse effects. A meta-analysis of 52 studies was carried out to assess the reported abundances of cytochrome P450 and uridine glucuronosyltransferase (UGT) enzymes in adult Caucasian subjects. Some heterogeneity was found between studies and the weighted means and overall coefficients of variation were calculated. Some strong enzyme expression correlations were identified; CYP3A4/CYP3A5*1/*3 (rs = 0.66, p < 0.0001, n = 37), CYP3A4/CYP2C8 (rs = 0.79, p < 0.0001, n = 107), and CYP2C8/CYP2C9 (rs = 0.71, p < 0.0001, n = 72). A quantitative protocol based on targeted proteomics was used to quantify cytochrome P450 and UGT enzymes in adult liver samples (n = 24). The QconCAT standard used for quantification was successfully expressed in-house after optimisation of the expression protocol, and the utility of two strategies in expressing recalcitrant QconCAT proteins was highlighted; the use of a fusion partner and reshuffling the order of peptides in the sequence. The enzymes quantified in this study were CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2D6, 2J2, 3A4, 3A5, 3A7, 3A43, and 4F2, and UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, and 2B15. Correlations of expression identified in the meta-analysis were confirmed and new correlations were demonstrated between UGT enzymes and between enzymes from the two families. Correlations between UGT enzymes were particularly strong and statistically significant. Relationships between enzyme expression levels and genotype, age, sex, smoking, and alcohol consumption were investigated. A significant effect of genotype on expression was seen for CYP3A5 (p < 0.0001). An overall moderate decline of expression with age was observed for all the enzymes under study; however, this relationship was not statistically significant in most cases. Gender did not have a considerable effect on expression, although some differences in expression were observed between male and female donors. Smoking seemed to induce the expression of all enzymes; however, statistically significant induction was demonstrated only in the cases of CYP2A6, CYP3A4, CYP3A7, and UGT1A1 (p < 0.05). Alcohol consumption was not shown to have a considerable effect on enzyme expression. Two pig livers were used to optimise some aspects of the experimental protocol including solubilisation and digestion of proteins. Pig MPPGL was measured and relative hepatic contents of drug-metabolising cytochrome P450 enzymes in pig liver were established using label-free quantification.

Heparan sulphate (HS) is critical for embryonic development with involvement in a myriad of biological processes, centrally mediating morphogenic movements and facilitating the specification and differentiation of tissues. Complicated by its structural micro-heterogeneity along with expression on numerous different proteoglycan cores, the plethora of roles for HS in biology and their underlying mechanisms have not yet been fully defined. The discovery and characterisation of new reagents and methods for modification of HS expression and/or structure will aid efforts in elucidating the structure and activity of this glycosaminoglycan. Until now, azido sugars have been utilised as labelling reagents for various types of glycosylation, including N-glycans, O-linked mucin-type glycosylation and O-GlcNAcetylation of proteins. Incorporation of the unnatural azido sugar into the glycan of interest inserts a chemically reactive abiotic azide for subsequent detection via Staudinger ligation or click chemistries. However, to our knowledge, application of these azido sugars has not been explored for glycosaminoglycans. A metabolic labelling approach using Ac4GalNAz yields UDP-GalNAz and UDP-GlcNAz (Boyce et al., 2011), ready to target CS/DS and HS, respectively. We hypothesised that HS synthesis might be altered in the presence of UDP-GlcNAz due to the location of the azide on the acetyl group and the potential for interference with endogenous N-deacetylase-N-sulphotransferase biosynthetic enzyme activity. In mammalian cell culture (Chinese hamster ovary cells), treatment with Ac4GalNAz led to a decrease in total HS abundance accompanied by significant increases in 6-O-sulphation within the chains. Incorporation of a radiolabelled metabolic precursor revealed that average HS chain length was decreased in azido sugar-treated CHO cells. The modifications to HS were dose-dependent and HS inhibition was transient. Following removal of Ac4GalNAz from cell culture, HS expression returned to baseline levels within 24 hours. Previous work from the Bertozzi group has demonstrated the utility of Ac4GalNAz for visualising GalNAc- and O-GlcNAc-modified proteins in vivo. Using Xenopus, we were able to show that treatment of fertilised eggs with Ac4GalNAz decreased the abundance of HS in a similar way to that seen in vitro, with an associated impact on embryonic development. Embryonic axial elongation was impaired, with defective myotomal development and aberrant axonal patterning along the trunk and tail. Posterior somite cell nuclei were disorganised, with loss of distinct chevron patterning and skeletal muscle development was impaired with muscle fibres spanning some of the somite boundaries. Removal of the inhibitor partially rescued tail extension defects, as well as muscle development, but not axonal patterning. Therefore, these experiments illustrate a novel application for Ac4GalNAz as a soluble and reversible inhibitor of HS synthesis for in vitro and in vivo studies. The observed potential for control of inhibition via time- and dose-dependent effects enables targeted and selective inhibition of HS and potentially provides a powerful new inhibitor for the study of HS-mediated events.

Des études cliniques rétrospectives ont suggéré un effet protecteur de l’anesthésie locorégionale contre les récidives après chirurgie carcinologique, donnant une nouvelle dimension à la prise en charge de la douleur périopératoire. Le premier objectif de ce travail était de montrer les effets antitumoraux directs de la lidocaïne, un anesthésique local couramment utilisé en pratique clinique. L’impact de la lidocaïne a été mesuré in vitro sur la viabilité, la prolifération et la migration de plusieurs lignées humaines de cellules de cancer du sein, ainsi qu’in vivo sur la progression métastatique péritonéale de cellules triple négatives. Le second objectif était de déterminer par quels mécanismes moléculaires la lidocaïne exerçait cette action antitumorale. Des approches globales par analyses transcriptomiques et métabolomiques ont mis en exergue de nouvelles hypothèses mécanistiques, en particulier relatives à des modifications de la composition lipidique des membranes cellulaires. Enfin une approche par gène candidat a suggéré un mode d’action de la lidocaïne indépendant du canal sodique voltage-dépendant. / Retrospective clinical studies have suggested a protective effect of regional anesthesia against recurrences after cancer surgery, bringing the management of perioperative pain to a new level. Prospective studies are underway to support these results. The first objective of this work was to show the direct antitumor effect of lidocaine, a local anesthetic commonly used in clinical practice. The impact of lidocaine was measured in vitro on viability, proliferation and migration of several human breast cancer cell lines, as well as in vivo on the metastatic peritoneal progression of triple negative cells. The second objective was to determine by which molecular mechanisms lidocaine exerts this antitumor action. Global approaches by transcriptomic and metabolomic analyses have highlighted new mechanistic hypotheses, notably in relation to the lipid composition of cell membrane. Finally, a candidate gene approach suggested that the mode of action of lidocaine is independent of the voltage-gated sodium channel.

Despite the ongoing political debate regarding the legality of medical marijuana, clinical investigations of the therapeutic use of cannabinoids are now more prevalent than at any time in history. Cannabinoids have been shown to have analgesic, anti-spasmodic, anticonvulsant, anti-tremor, anti-psychotic, anti-inflammatory, anti-oxidant, anti-emetic and appetite-stimulant properties. There are mainly two well-known cannabinoid receptors, CB1 and CB2, located in the central (CB1) and peripheral (CB2) nervous systems as well as the immune system. More recently, endocannabinoids (ligands) and their receptors have also been found in the skeleton which appear as the main body system and physiologically regulated by CB2. This study aimed to examine the effect of both CB1 and CB2 receptor stimulation on wound closure response of MG-63 osteoblast bone cell monolayers using different treatments with cannabinoid such as Winn55,212-2, URB602 and HU308. Also, cell adhesion, cell proliferation and cell length was investigated. The study also aimed to examine the effect of HU308 treatments in combination with TGF-β3 (transforming growth factor beta -3) on wound healing, cell adhesion and extracellular matrix up regulation (collagen type I, fibronectin and protien S-100A6) as well as other biological factors such as secretion of matrix metalloproteinase (MMP-2) and nitric oxide (NO). Finally, this study investigated HU308/TGF-β3 combination treatment on the regulation of extracellular matrix (collagen type I, fibronectin and protien S-100A6) in a 3D multilayer system of MG-63 osteoblast bone cells. Wound healing assays of MG-63 monolayers revealed accelerated wound repair as well as increased cell proliferation mainly regulated through CB2 receptors, and that treatments with HU308 and HU308/TGF-β3 achieved minimum closure timings compared with control groups (P<0.05). Our finding suggested that proliferation rate with 500nM HU308 was significantly higher than control and TGF-β3/HU308 combination groups (P<0.05). Interestingly, percentage of wound remained open after 15 hours for combination groups was 17.6%±1.32 whereas treatment with 500nM HU308 had 20%±2.25 indicating that the combination groups took the lead throughout wound healing. It was also observed that bridge formation in all treatment groups was taking place between 15 to 20 hour periods whereas within control treatments bridge formation started to take place after 25 hours. Cell surface attachment was examined via the trypsinization assay in which the time taken to trypsinize cells from the surface provided a means of assessing the strength of attachment. The results indicated that higher concentrations of HU308 (2μM), induced significant force of cell attachment compared with control and concentrations of 500nM and 1μM (P<0.05). However, groups treated with TGF-β3 and combination HU308/TGF-β3 indicated reduced cell surface attachment compared with control groups, indicating enhanced cell migration. Immunofluorescence staining as well as Elisa based semi-quantification technique indicated that both collagen type I and fibronectin were unregulated using higher concentrations of HU308 with decreased cell proliferation compared to lower concentrations. Nevertheless, protein S-100A6 was up-regulated in treatments with HU308, TGF-β3 and their combination HU308/TGF-β3 (P<0.05), indicating the positive role of these treatments in promoting cell differentiation. MMP-2 levels in the current study were also shown to be concentration-dependent, i.e. higher concentrations of HU308 significantly reduced MMP-2 secretion leading to decreased cell migration, while HU308/TGF-β3 combination treatment increased MMP-2 levels, indicating an increase in cell migration. The current study also examined levels of nitric oxide synthesis in relation to different treatments with HU308, TGF-β3 and HU308/TGF-β3 combination. It was found that nitric oxide up-regulation influences rate of MG-63 osteoblast wound healing in a concentration dependent manner. Lastly, UpCell culture dishes proved to have efficacy in obtaining a multilayer model of MG-63 osteoblast system in-vitro through changes in cell morphology. It was also found that treatments with HU308, TGF-β3 and HU308/TGF-β3 combination influenced collagen type I, fibronecton and protein S-100A6 secretion. These findings supported the earlier Elisa based semi-quantification results obtained for monolayer cultures.

La dépression est un trouble neurologique grave et la deuxième cause d’invalidité dans le monde. Récemment, la signalisation du récepteur X aux rétinoïdes et l’inflammation chronique ont été identifiées comme facteurs génétiques et environnementaux. Au cours de ma thèse, j'ai étudié la façon dont le récepteur X gamma aux rétinoïdes (RXRg) contrôle la neuroinflammation dans deux modèles précliniques de dépression. J'ai montré que RXRg contrôle un signal spécifique lié à l'âge, entrainant la sénescence et l'hypoactivité des cellules microgliales. Ce signal impacte également la phagocytose microgliale et contribue à l'hypertrophie neuronale dans le striatum, elle-même associée à des symptômes dépressifs. De plus, j'ai pu mettre en évidence une activité antidépressive des rexinoïdes et des fibrates dans le stress de défaite sociale chronique, ainsi que leur mécanisme cellulaire. Les données obtenues pourraient permettre le développement de nouveaux traitements antidépresseurs. / Depression is severe mental disorder that is a second leading contributor to diseases burden. Recently, retinoid X receptor signaling and chronic inflammation have been identified as genetic and environmental factors. However, a cross-talk between these two factors was poorly understood. During my PhD I have studied how retinoid X receptor gamma (RXRg) controls neuroinflammation in two pre-clinical models of depression. I have shown that RXRg controls age-specific signal that drives microglial senescence and hypoactivity. The latter, impacts also microglial phagocytosis and contribute to neuronal hypertrophy in the striatum that previously was associated with depressive symptoms. Additionally, I showed antidepressant activity and cellular mechanism of rexinoids and fibrates in chronic social defeat stress. Obtained data have strong therapeutic potential that may allow for development of new antidepressant therapies.

En raison de l’efficience des traitements, le taux de survie globale à 5 ans des patients avec un cancer gastrique (CG) est d’environ 15%. A l’heure actuelle, il n’existe pas de stratifications des patients permettant de prescrire un protocole de traitements efficace. Durant ma thèse, j’ai établi le rôle de HDAC4 dans la sensibilité des cellules de CG au Cisplatine. J’ai montré que cette réponse semble dépendre du type de CG (intestinal ou diffus) et du statut p53 des cellules cancéreuses. J’ai souligné l’intérêt de combiner un inhibiteur des HDACs (SAHA) avec les chimiothérapies à base de dérivés de platine (PDC : Cisplatine, Oxaliplatine) afin de promouvoir leurs effets cytotoxiques. De manière intéressante, j’ai observé que la réponse aux traitements combinés est différente suivant le statut p53 des cellules cancéreuses. Ces résultats permettent d’ouvrir de nouvelles perspectives dans l’utilisation des traitements combinés PDC + SAHA dans la thérapie du CG. En particulier, le facteur p53 qui est souvent muté dans les CG, pourrait être un marqueur thérapeutique pour un tel protocole de traitement. / Due to the efficiency of treatments, the 5-year overall survival rate for patients with gastric cancer (GC) is approximately 15%. Currently, there is no stratification of patients to prescribe an effective treatment protocol.During my thesis, I established the role of HDAC4 in the sensitivity of GC cells to Cisplatin. I have shown that this response seems to depend on the type of GC (intestinal or diffuse) and the p53 status of cancer cells. I emphasized the interest of combining an HDAC inhibitor (SAHA) with platinum derivative chemotherapies (PDC: Cisplatin, Oxaliplatin) to promote their cytotoxic effects. Interestingly, I observed that the response to combination treatments is different depending on the p53 status of the cancer cells.These results open new perspectives in the use of PDC + SAHA combination therapies in GC. The p53 factor that is often mutated in GC could be a therapeutic marker for a such treatment protocol.

Les maladies cardiovasculaires (MCV) sont la première cause de décès dans le monde. Les problèmes majeurs dans la gestion de ces patients sont le diagnostic et la prédiction du pronostic. Les microARN (miARN) sont de petits ARN simple brin non codants qui inhibent l’expression des gènes. Les miARN circulants sont apparus comme biomarqueurs potentiels des MCV. Les miARN pourraient être également utiles pour la réparation cardiaque post infarctus du myocarde (IM). Nous avons émis l’hypothèse que les miARN pourraient être utilisés comme biomarqueurs des MCV et outils thérapeutiques dans la réparation cardiaque post-IM. Nous avons évalué la capacité diagnostique des miARN chez des patients avec douleurs thoraciques. Les miR-208b et miR-499 sont de potentiels biomarqueurs diagnostiques chez les patients avec IM mais n’améliorent pas la valeur diagnostique des biomarqueurs traditionnels. Le miR-423-5p permet de prédire la réhospitalisation des patients atteints d’insuffisance cardiaque aiguë et les miR-21 et miR-122 sont associés aux séquelles neurologiques de patients après arrêt cardiaque. Les miARN circulants seraient de potentiels biomarqueurs diagnostiques/pronostiques des MCV. Nous avons également montré qu’inhiber le miR-16 permet de stimuler la prolifération, la différenciation et les capacités pro-angiogéniques des cellules endothéliales progénitrices et que le miR-150 est impliqué dans l’effet de l’adénosine sur leur recrutement post-IM. Les miARN pourraient être utilisés pour améliorer la revascularisation post-IM. En conclusion, nos études contribuent à la caractérisation de plusieurs miARN dont l’utilité clinique dans le domaine cardiovasculaire reste à confirmer. / Cardiovascular diseases are the leading cause of death in the world. Major issues in the management of these patients lie on the diagnosis and the prediction of the prognosis. MicroRNAs (miRNAs) are small single-stranded non-coding RNAs that inhibit gene expression. Circulating miRNAs appeared as potentials biomarkers of cardiovascular diseases. MicroRNAs could be also useful to stimulate cardiac repair. We hypothesized that miRNAs could be used as biomarkers of cardiovascular diseases, and also as therapeutic tools to improve cardiac repair after myocardial infarction. We evaluated the diagnostic capacity of miRNAs in patients with chest pain. MicroRNA-208b and miR-499 were potential diagnostic biomarkers in patients with myocardial infarction, without improving the diagnostic accuracy of traditional biomarkers. MicroRNA-423-5p predicted the rehospitalization of patients with acute heart failure and miR-21 and miR-122 are associated with neurological damage after cardiac arrest. Overall, our results indicate that circulating miRNAs could be useful diagnostic and prognostic biomarkers of cardiovascular diseases. We also showed that inhibiting miR-16 could stimulate the proliferation, differentiation and pro-angiogenic capacities of endothelial progenitor cells and that miR-150 is involved in the effect of adenosine on the recruitment of these cells after myocardial infarction. These results suggest that miRNAs could be used to improve the revascularization after myocardial infarction. In conclusion, our studies contributed to the characterization of several miRNAs, which clinical utility in the cardiovascular field remains to be confirmed.

Un des écueils du traitement des pathologies ostéoarticulaires est l’adressage de molécules aux cellules et tissus qui constituent l’articulation. L’administration de principes actifs par voie sanguine ou orale nécessite l’apport de quantités importantes et peut causer des effets indésirables. Dans ces travaux, nous avons évalué un système d’adressage de molécules hydrophiles. Des particules de polymère d’acide lactique et glycolique, marquées par un traceur fluorescent ont été évaluées in vitro puis in vivo. Ces particules possèdent un recouvrement en acide hyaluronique pour améliorer les interactions avec les cellules. Les études réalisées ont permis de mettre en évidence l’internalisation des particules dans les synoviocytes, chondrocytes, et cellules souches mésenchymateuses après 8 heures d’exposition. Parallèlement, l’évaluation in vitro de différents paramètres de cytotoxicité et d’inflammation a permis de souligner la compatibilité de ces vecteurs avec les cellules articulaires. Enfin, les effets de l’injection intra-articulaire de particules ont été évalués chez le rat sain et différents modèles pathologiques. L’analyse histologique des articulations a démontré l’absence de dégradation de la matrice cartilagineuse et de réaction inflammatoire suite à l’injection de particules. Il a été également constaté un ciblage majoritaire des particules vers la membrane synoviale. Ces travaux permettent de valider l’utilisation de ce type de vecteur pour le ciblage de l’articulation et l’apport de principes actifs. L’association de ces particules à des molécules hydrophiles (acides nucléiques, médicaments,…), pourra permettre leur apport direct dans l’articulation et ouvrir de nouvelles perspectives thérapeutiques. / One of the major issues with treatment of osteoarticular diseases is reaching cells or tissue inside the joint. Administration of an active compound by intravenous or per os requires elevated amount to be effective, and can initiate systemic and negative side effects. In this work we have evaluated a drug delivery system for hydrophilic molecule, which can be used for articular tissues. Polymeric nanoparticles of poly lactic-co-glycolic acid, labelled with a fluorescent dye were evaluated both in vitro and in vivo. These nanoparticles are covered with hyaluronic acid to favor particles-cells interaction. We demonstrated here that such particles are internalized after 8 hours of exposure in synoviocytes, chondrocytes and mesenchymal stem cells. Evaluation of cytotoxicity and inflammation revealed the neutrality of these particles for articular cell types. Finally, intraarticular injections of particles were performed in healthy rat joint and in pathological models. Histological analyses of extracellular matrix integrity and inflammatory status do not demonstrate any side-effect following particles injections. These healthy nano-device target primarily synovial cells, and their degradation inside cells does not provoke deleterious effects. This PLGA based drug delivery system would be used to safely deliver active molecules to the joint. The combination of these particles with various hydrophilic molecules (as nucleic acid, drugs,…) may allow their direct distribution in the joint, and lead to new therapeutics perspectives.