Microbial shifts in the aging mouse gut

YesBackground: The changes that occur in the microbiome of aging individuals are unclear, especially in light of the imperfect correlation of frailty with age. Studies in older human subjects have reported subtle effects, but these results may be confounded by other variables that often change with age such as diet and place of residence. To test these associations in a more controlled model system, we examined the relationship between age, frailty, and the gut microbiome of female C57BL/6 J mice. Results: The frailty index, which is based on the evaluation of 31 clinical signs of deterioration in mice, showed a near-perfect correlation with age. We observed a statistically significant relationship between age and the taxonomic composition of the corresponding microbiome. Consistent with previous human studies, the Rikenellaceae family, which includes the Alistipes genus, was the most significantly overrepresented taxon within middle-aged and older mice. The functional profile of the mouse gut microbiome also varied with host age and frailty. Bacterial-encoded functions that were underrepresented in older mice included cobalamin (B12) and biotin (B7) biosynthesis, and bacterial SOS genes associated with DNA repair. Conversely, creatine degradation, associated with muscle wasting, was overrepresented within the gut microbiomes of the older mice, as were bacterial-encoded β-glucuronidases, which can influence drug-induced epithelial cell toxicity. Older mice also showed an overabundance of monosaccharide utilization genes relative to di-, oligo-, and polysaccharide utilization genes, which may have a substantial impact on gut homeostasis. Conclusion: We have identified taxonomic and functional patterns that correlate with age and frailty in the mouse microbiome. Differences in functions related to host nutrition and drug pharmacology vary in an age-dependent manner, suggesting that the availability and timing of essential functions may differ significantly with age and frailty. Future work with larger cohorts of mice will aim to separate the effects of age and frailty, and other factors.This work was supported by the Canadian Institutes of Health Research (CIHR) through an Emerging Team Grant to RGB, CIHR Operating Grants to Langille et al. Microbiome 2014, 2:50 Page 10 of 12 http://www.microbiomejournal.com/content/2/1/50 SEH (MOP 126018) and RAR (MOP 93718), and a CIHR Fellowship to MGIL. Infrastructure was supported by the Canada Foundation for Innovation through a grant to RGB. RGB also acknowledges the support of the Canada Research Chairs program

Etude de systèmes moléculaires programmés pour la libération sélective d'agents anticancéreux

Le problème majeur de la chimiothérapie anticancéreuse conventionnelle réside dans la faible sélectivité des agents cytotoxiques vis-à-vis des tumeurs, entrainant de sévères effets secondaires et un phénomène de résistance pleïotropique. L'utilisation de prodrogues, activées sélectivement au niveau de la tumeur par la b-glucuronidase, au cours d'un protocole ADEPT (Antibody Directed Enzyme Prodrug Therapy) ou PMT (Prodrug Mono Therapy), permet de limiter ce problème. Ainsi, une prodrogue glucuronylée de la doxorubicine, HMR 1826, s'est révélée être plus efficace que l'agent actif correspondant au cours du traitement de nombreuses tumeurs in vivo. Ces travaux de thèse s'inscrivent dans la continuité de ces résultats avec pour objectif d'améliorer le concept des prodrogues glucuronylées. Dans une première partie, ce concept a été appliqué aux HDACi avec la synthèse et l'évaluation biologique d'une prodrogue glucuronylée de MS-275. La deuxième partie est consacrée à l'étude d'une nouvelle structure dendritique auto-immolable permettant de vectoriser deux agents anticancéreux de même nature ou de nature différente et d'assurer leur libération après une seule hydrolyse enzymatique. Les études biologiques ont permis de valider le potentiel de cette approche. Ce concept a été étendu aux dimères de cyclodextrines, pour permettre le transport de l'agent actif sans liaison covalente. Enfin, la troisième partie du manuscrit est consacrée à l'étude d'un système permettant le ciblage de deux particularités tumorales spécifiques aux cellules et au microenvironnement.The major problem with conventional cancer chemotherapy is the low selectivity of cytotoxic agents against tumors, causing severe side effects and pleiotropic resistance. To overcome these drawbacks, prodrugs have been developed to be selectively activated at the tumor site by b-glucuronidase during an ADEPT (Antibody Directed Enzyme Prodrug Therapy) or a PMT (Prodrug Mono Therapy) protocol. Within this framework, the glucuronylated prodrug of doxorubicin, HMR 1826, has demonstrated superior efficiency during the treatment of various human xenografs in mice compared to standard chemotherapy. In the course on this PhD new approaches have been developed to improve the scope of glucuronylated prodrugs. The first part of this work describes the synthesis and biological studies for a glucuronylated prodrug of MS-275. The second part is devoted to the study of a new self-immolative dendritic structure designed to target two cytotoxic molecules, even different, and to release the drugs after a single enzymatic hydrolysis. Biological studies have validated the potential of this approach. This concept has been extended to cyclodextrin dimers, to allow the transport of active agent without covalent bonds. Finally, the last approach of the manuscript is devoted to the study of a system suitable for targeting cells and micro-environment specificities of the tumor.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Synthèse d'analogues d'inhibiteurs d'histone désacétylases

POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Synthèse d'édifices supramoléculaires dédiés à la vectorisation d'agents thérapeutiques

La vectorisation d agents thérapeutiques vers leur zone d action est un axe de recherche important et plus particulièrement dans le domaine du cancer. Il est important de concevoir des systèmes moléculaires capables de transporter des drogues de façon inoffensive vis-à-vis des tissus sains et de déclencher l activation de l agent antitumoral uniquement lorsque la tumeur est détectée. Les travaux présentés dans ce mémoire de thèse portent sur l emploi de cyclodextrines dans la conception d édifices supramoléculaires pour la vectorisation d agents thérapeutiques. Les cyclodextrines peuvent solubiliser un principe actif, modifier sa disponibilité en interagissant avec les membranes cellulaires, améliorer sa pharmacocinétique ou encore cibler son action thérapeutique. Un édifice moléculaire basé sur les cyclodextrines et dédié à la vectorisation peut être envisagé autour de trois parties : la cyclodextrine, un espaceur et le vecteur. Une première partie de ce travail concerne le choix de l espaceur, car il doit apporter au système un maximum d efficacité, que ce soit en complexation, en solubilisation ou en vectorisation. Concernant la vectorisation, le concept des prodrogues auto-immolables a été largement étudié. Notre second objectif est d associer le concept des cyclodextrines avec celui des prodrogues pour concevoir de nouveaux édifices supramoléculaires dédiés à la vectorisation de drogues. La synthèse de dimères de cyclodextrines auto-immolables sera présentée ainsi que les premiers résultats concernant le potentiel de ces édifices dans la capture, la solubilisation et la vectorisation de droguesSite-specific delivery of clinically used drugs is an important aspect of research, particularly in the field of cancer treatment. It s important to design molecular systems capable of transporting drugs in an innocuous fashion for healthy tissues and with the activation of the therapeutic agent only at the tumour site. The presented work consists of the use of cyclodextrins in the conception of supramoleculars structures for the targeting of therapeutics agents. Cyclodextrins have been known to solubilize active compounds, enhance their bioavailability by interactions with the cell surface, improve their pharmacokinetic profile and drug targeting. Such a system can be separated into three distinct portions namely: the cyclodextrin, a spacer and a ligand. The first objective of this work was the choice of the spacer arm because it should result in an efficient system capable of optimal complexation, solubilization and vectorization. In the field of drug-targeting, the concept of self-immolative prodrugs has been widely studied. Our main objective was to associate the advantages of cyclodextrins with that of prodrugs in order to create new supramoleculars structures dedicated to drug targeting. The synthesis of these self-immolative cyclodextrins dimers shall be detailed, as well as the preliminary results concerning the capacity of these structures to capture, solubilize and vectorize an antitumorous drugPOITIERS-BU Sciences (861942102) / SudocSudocFranceF

A self-immolative dendritic glucuronide prodrug of doxorubicin

International audienceThe first self-immolative dendritic glucuronide prodrug of doxorubicin was studied with the aim to target beta-glucuronidase overexpressed in the microenvironment of numerous tumors. This compound includes a chemical amplifier programmed to release two molecules of doxorubicin after a single enzymatic activation step. Upon beta-glucuronidase activation, the dendritic prodrug was twice more toxic than its monomeric counterpart against H661 lung cancer cell

Rotaxane-based architectures for biological applications

International audienceRécemment, le développement de rotaxanes pour des applications biologiques a suscité un intérêt grandissant. Dans cette mise au point, nous résumons les principaux progrès qui ont été réalisés dans ce domaine, en décrivant successivement les rotaxanes encapsulant des squaraines pour l'imagerie biologique, les rotaxanes hôtes comme agents de transport cellulaire, les rotaxanes enzymo-sensibles et les nanoparticules de silice mésoporeuse revêtues de « nanovalves » pour la délivrance de médicaments

The Lossen rearrangement from free hydroxamic acids

International audienceThe Lossen rearrangement, that allows the conversion of hydroxamic acids into isocyanates, was discovered almost 150 years ago. For more than a century, this transformation was supposed to occur exclusively in the presence of stoichiometric amounts of activating reagents devoted to promoting the dehydration of primary hydroxamic acids. Very recently, it was demonstrated that the Lossen rearrangement can take place directly from free hydroxamic acids offering a renewal of interest for such a reaction. This short review summarizes advances in this field by describing successively the metal-assisted, the self-propagative and the promoted self-propagative Lossen rearrangement with a special emphasis on their mechanisms

Design of self-immolative linkers for tumour-activated prodrug therapy

The main drawback of most cancer chemotherapy is its relatively low ability to target tumour cells versus normal cells. As a consequence, chemotherapy is usually connected with severe side effects due to the toxicity of traditional cytostatic agents towards normal tissues. A few years ago, the site-specific activation of non-toxic prodrugs in tumours has been proposed in order to enhance the selectivity for the killing of cancer cells. Within this framework, most of the prodrugs that have been designed were three part compounds comprising trigger, linker and effector units. The main function of the linker is to release the effector unit after selective trigger activation via a spontaneous chemical breakdown. However, its structure also affects significantly many prodrug properties such as stability, pharmacokinetic, organ distribution, bioavailability or trigger activation. This review, focussed on the linker unit, is an update of our previous article published in 2002. It deals with recent advances in the design of prodrug linkers including new delivery systems such as elongated linkers or self-immolative dendrimers