ECOLE DOCTORALE "Médicament, Toxicologie, Chimie, Imageries" - UNIVERSITE PARIS DESCARTES Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2014-2015 Version word sans signature pour le site et version papier signée. Renseignements relatifs à l’Unité de Recherche : Nom et appartenance : Laboratoire de chimie et biochimie pharmacologiques et toxicologiques – CNRS UMR 8601 Nom et prénom du Directeur : ACHER, Francine C. Téléphone : +33 (0)1 42 86 33 21 courriel : [email protected] Signature obligatoire :(et avis éventuel) : Renseignements relatifs à l’Equipe d’Accueil (EAD) : Nom de l’Equipe d’Accueil : Synthèse organique pour la recherche biomédicale Nom et prénom du responsable : GRAVIER-PELLETIER, Christine Qualité du responsable : DR2, CNRS Téléphone : + 33 (0)1 70 64 99 71 courriel : [email protected] Signature obligatoire: Renseignements relatifs au sujet de thèse : Nom et prénom du Directeur de thèse (HDR) : DHIMANE, Hamid et DALKO, Peter I. Qualité : PR2 et DR2 Téléphone : +33 (0)1.42.86.22.65 courriel : : [email protected]; [email protected] Signature obligatoire :. Titre du sujet proposé : X- and Gamma-Sensitized Nano Release Systems for Image Guided Drug Delivery Préciser le secteur disciplinaire (402, 510, 530)* principal et éventuellement secondaire : 402 Résumé succinct (5 lignes maximum) : The project aims to finalize the development of a novel class of multisite device that allows targeted delivery of virtually unrestricted variety of compounds deep within the body. The method has the ability to follow the distribution and the liberation in real time by different bioimaging modalities. While the application promises impact in many areas, two shortcomings need to be addressed: 1) The sensitivity of the probe needs to be ameliorated; 2) The overall residence time of the probe demands to be optimized. Demande dans le cadre d’un projet ANR (donner toutes précisions utiles) : Le projet a été soumis à l’AAP 2014 Allocations de la Région IdF - DIM Nano-K 1 Merci de retourner ce document par e-mail à [email protected] ECOLE DOCTORALE "Médicament, Toxicologie, Chimie, Imageries" - UNIVERSITE PARIS DESCARTES Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2014-2015 (l'ensemble de cette fiche ne doit pas dépasser 1 page) Nom, prénom du directeur de l'unité de recherche : ACHER, Francine C. Numéro de l'unité de recherche (et établissement de rattachement) : CNRS UMR 8601 Nom, prénom du responsable de l'équipe d'accueil (EAD) : GRAVIER-PELLETIER, Christine Nom, prénom du directeur de thèse : DHIMANE, Hamid et DALKO, Peter I. Titre du sujet de thèse proposé : X- and Gamma-Sensitized Nano Release Systems for Image Guided Drug Delivery Contenu scientifique du programme de la thèse Medical applications in nanotechnology are a rapidly growing segment with significant impact on diagnosis and therapeutics for the treatment of human diseases. Nanoparticle (NP) based drug delivery is of particular interest as these materials may show prolonged circulation half-life, reduced non-specific uptake, and increased accumulation in specific tissues and organs through enhanced permeation and retention (EPR). Among the number of NP-based therapeutic approaches the delivery of an active compound by external trigger “on demand” and the intrinsic chemical and biochemical stimuli gated drug release are of particular interest. Nano-systems allowing “on demand” liberation are relying on stimuli responsive (also termed “smart”) materials triggered by pH, temperature modifications, variation of magnetic fields, or, light irradiation. Some of these methods can be applied in good spatio-temporal control, by which a high level of drug concentration (six- to ten fold) can be eventually attained. Although this strategy promises considerable advantages in term of reduced general toxicity and diminished resistance against the drug, the field is still in infancy: external activation of prodrugs with localized liberation of compounds stays a major challenge. We developed a method that allows external stimuli-gated delivery in deep tissues of virtually unrestricted variety of compounds having therapeutic interest with the ability to follow the distribution and the liberation in real time by different bioimaging modalities with the potential for multimodality.[1] [2] While the method promises impact in many medical area two shortcomings need to be addressed for further translation: (1) The sensitivity of the probe needs to be ameliorated to meet current radio-safety recommendations; (2) The overall residence time of he device demands to be increased. In order to bring ameliorations, the project suggests to test a series of new redox fragmenting elements, and also to replace the original polar organometallic complex by charge-neutral NPs. Two NP platforms are considered here: iron oxide and gold NPs, which are among the few nanomaterials that are nontoxic, bio-compatibles and approved for therapeutic use. Noteworthy, both types of nanoparticles can be imaged. Domains of typical applications could be, for example treatment of inflammation, drug abuse, where intracellular drug-delivery is needed and also in cancer therapy, where the major part of the required instrumentation is already implemented. Biomedical applications are only part of the potential field of interest, as the method may find application in microfabrication where 3D controlled manipulations in high spatial resolutions are needed in inaccessible spaces. [1] (a) Petit, M.; Bort, G.; Doan, B.-T.; Sicard, C.; Ogden, D.; Scherman, D.; Ferroud C.; Dalko, P. I. Angew. Chem. Int. Ed. 2011, 50, 9708–9711. For light-gated delivery see: (b) G. Bort, T. Gallavardin, D. Ogden, P. I. Dalko, Angew. Chem. Int. Ed. 2013, 51, 4526–4537; (c) M. Petit, C. Tran, T. Roger, T. Gallavardin, H. Dhimane, F. Palma-Cerda, M. Blanchard-Desce, F. C. Acher, D. Ogden, P. I. Dalko, Org. Lett. 2012, 14, 6366–6369. [2] X-Ray and Gamma-Photon Activable Organic Compounds, Their Preparation and Their Uses; Peter Dalko, Morgane Petit, David Ogden, Guillaume Bort, Cécile Sicard; WO/2011/158189; EP2582672A1; US 2013/0190284.