Drogue | EPFL Graph Search

Une est un composé chimique, biochimique ou naturel, capable d'altérer une ou plusieurs activités neuronales et/ou de perturber les communications neuronales. La consommation de drogues par l'Homme – afin de modifier ses fonctions physiologiques ou psychiques, ses réactions physiologiques et ses états de conscience – n'est pas récente. Certaines drogues peuvent engendrer une dépendance physique ou psychologique. L'usage de celles-ci peut avoir pour conséquences des perturbations physiques ou mentales. Pour désigner les substances ayant un effet sur le système nerveux, il est plus généralement question de psychotrope. Le terme « drogue » recouvre essentiellement deux aspects : la nature des effets biologiques que la drogue induit d'une part et, d'autre part, les rapports que celui qui la consomme entretient avec elle. Il faut qu'un composant chimique donné soit consommé pour qu'il puisse répondre à l'appellation de « drogue ». Le mode et la fréquence de consommation influe directem

Microdevice-integrated immunoassays for Point-of-Care Therapeutic Drug Monitoring

Elena-Diana Bojescu

A significant number of drugs exhibit narrow therapeutic windows and high inter-individual pharmacokinetic variability. In such cases, Therapeutic Drug Monitoring (TDM) is compulsory in order to optimize the efficacy of the drug while avoiding adverse effects. Concentration measurements required for dose-adjustments are however complex and are therefore only performed at specialized facilities. The development of a device for accurate whole-blood quantification of critical drugs at the Point-of-Care (POC) would enable fast time-to-result and provide a more convenient solution to patients. This thesis aimed at the design of sample-to-result devices comprising microstructures that allowed for the quantification of small molecules in blood. The designs were based on the development and use of miniaturized fluorescence polarization immunoassays (FPIA). The main feature offered by the FP assay format was the ability to perform homogeneous measurements with no separation or washing steps required. An important result of this thesis is the demonstration that the concentration of small drugs can be quantified in whole blood within paper-like membranes using Fluorescence Polarization Immunoassay (FPIA). Different types of paper-like materials such as glass microfibers, cellulose and filter paper were screened for artefacts such as scattering or autofluorescence. Accurate determination of the fluorescence polarization of red-emitting fluorophores at sub-nanomolar concentrations was found possible within glass fiber membranes. This enabled the development of a competitive immunoassay for the quantification of the antibiotic tobramycin using only 1 ïL of plasma in glass fiber micro-chambers. Furthermore, the same membrane was used for transversal separation of blood cells followed by accurate FPIA read-out at the bottom part of the micro-chamber. Within the therapeutic window, coefficients of variation were around 20% and recoveries between 80-105%, demonstrating the ability to run quantitatively both clinical chemistry and sample preparation by incorporating FPIA in glass fiber membranes. Another important step towards a POC device was the design of a compact, bench-top FP-based analyzer. In this case, glass capillaries were used as detection chambers as they cause little light scattering and for reasons of convenience. Furthermore, the new optical system was employed for tobramycin quantification previously spiked in plasma samples showing good analytical performance in terms of coefficients of variation and recoveries within the therapeutic range of the drug. A more challenging class of drugs are the immunosuppressants, administered in cases of organ transplantation. Here, several fluorescent derivatives of tacrolimus at different wavelengths were synthesized. Their affinity for various biorecognition molecules were tested allowing the choice of a ligand-receptor pair for the development of a FPIA for tacrolimus quantification in buffer. Next, attempts were undertaken to adapt the immunoassay for analysis in whole blood samples. Considerable challenges due to the complexity of the matrix were revealed and initiated efforts to improve the whole blood preparation techniques with the aim of quantifying tacrolimus within its therapeutic range. With the aim of paving the way towards personalized therapies, this thesis makes the realisation of a POC for TDM a realistic goal.

EPFL2018

Repurposed drug combination via high-throughput screening and dual drug delivery system development for the treatment of retinoblastoma

Po-Jen Tseng

The goal of retinoblastoma (RB) treatment is to save the child's life, eyes and functional vision, with that order of priority. The management of RB is complex and involves strategically chosen methods of surgical enucleation, external beam radiotherapy, intravenous chemoreduction and focal therapy. Local administration routes of chemotherapy, intra-arterial (IAC) and intravitreal (IVC), have emerged as promising methods to salvage the eyes and vision. New improvements in the chemotherapy of RB are geared towards reducing side effects of the drugs employed. Emerging strategies includes alternative chemotherapeutic agents, drug combinations, and novel drug delivery systems. Most successful examples of drug repurposing so far have been serendipitous. The systematic approach here was identified candidate drugs by strategic high-throughput screening methods. In this thesis, hit drugs were screened from a drug library of primarily FDA-approved drugs, and the synergistic effect of selected drug combinations was investigated. The hit drug gemcitabine, known to be an effective clinical treatment for non-small cell lung cancers, in combination with carboplatin, was discovered to have the highest cytotoxicity of the hits identified, and appeared as a potential alternative therapeutic agent for RB treatment.Polymeric nanoparticles (NPs) as an improved drug delivery system were investigated with gemcitabine. The nanoprecipitation synthesis of a poly(lactic-co-glycolic acid), as known as PLGA, nanoparticle was developed for drug encapsulation. The characterization of PLGA NPs within various active pharmaceutical ingredients were studied using dynamic light scattering and scanning electron microscopy, revealing that spherical NPs ranging in size from 150 to 200 nm could be successfully prepared. The tumor cells proliferation inhibition was observed after treatment with this novel nanoformulation. Furthermore, the possibility of a dual drug delivery system was explored. Gemcitabine and carboplatin were encapsulated together in PLGA NPs and found to show a synergistic effect after dual drug release. Additionally, gemcitabine combined with the light-activated agent indocyanine green was prepared, and laser-induced photothermal therapy (PTT) was explored.

EPFL2022

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

Malignant gliomas represent 80% of tumors developing in the central nervous system, with 50% being glioblastomas (GBM), the most aggressive form of the disease. The benefit from current therapies is very limited, the overall 5-year survival rate of patients with GBM being less than 5%. Thus, there is an urgent need for better therapies. It has been reported that the use of tricyclic antidepressants (TCAs) is linked with reduced incidence of gliomas. In line with these observations, our lab previously demonstrated that combining imipramine (IM), a TCA that activates adenylate cyclase and elevates production of cAMP, with ticlopidine (TIC), an inhibitor of the purinergic receptor P2Y12 that otherwise suppresses cAMP, results in a concerted increase in the levels of intracellular cAMP, which consequently stimulates increased autophagy in glioma cells, leading to autophagy-associated cell death (AACD) in culture and during orthotopic tumor growth. In several mouse models of glioma, the combination improved survival and reduced malignant grade. Seeking to assess the therapeutic translational potential of these repurposed drugs, particularly IM, we performed pre-clinical trials combining IM+/-TIC with anti-VEGF therapy, which is commonly used in patients with GBM; such anti-angiogenic therapy is associated with a transitory improvement in progression-free survival and quality of life, but does not translate into an overall survival benefit. Using genetic mouse models with enabling bioluminescent monitoring of the cancer cells, we treated established GBMs with imipramine, ticlopidine, and B20S, an anti-mouse VEGF monoclonal antibody. We observed transient stabilization of tumor growth, and the overall survival was significantly extended in the regimens combining B20S with IM +/- TIC compared to control and single treatments. Similar to clinical observations in GBM patients treated with anti-angiogenic therapy, mice treated with B20S alone had no survival benefit, implicating a synergetic effect for the combination of anti-VEGF treatment with imipramine and ticlopidine. We found that the combinatorial therapy elicited further increases in autophagy and displayed some indication of blood vessel normalization, concomitant with an elevation of CD8+T lymphocyte infiltration into the orthotopic tumors. Notably, we could partially reverse the beneficial effect of the combinations using a CD8+T cell-depleting antibody, revealing the involvement of the recruited CD8+T cells in the efficacy of the combinatorial treatment, in addition to the cell-intrinsic autophagy-associated death that is demonstrable in culture and in tumors. Together, these results suggest a strategy to improve anti-angiogenic therapy in patients with glioblastoma, by using repurposed FDA-approved drugs that markedly elevate autophagy in concert with anti-VEGF therapy. The recruitment of CD8+ T cells into the treated tumors and their evident contribution to therapeutic efficacy motivates ongoing experiments aimed to heighten and sustain the induced anti-tumor immune response.

EPFL2018

Repurposed drug combination via high-throughput screening and dual drug delivery system development for the treatment of retinoblastoma

Po-Jen Tseng

EPFL2022

Microdevice-integrated immunoassays for Point-of-Care Therapeutic Drug Monitoring

Elena-Diana Bojescu

EPFL2018

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

EPFL2018