Nanotechnologies for the Treatment of Severe Diseases

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Multicellular tumor spheroids: a relevant 3D model for the in vitro preclinical investigation of polymer nanomedicines

International audienceThe application of nanotechnology to medicine, usually termed nanomedicine, has given a crucial impulse to the design of various drug-loaded nanocarriers driven by the aim to overcome the limits associated with traditional drug delivery modalities, in particular, in the field of cancer treatment. However, an appropriate preclinical evaluation of the real therapeutic potential of nanomedicines suffers from the lack of relevant models that are well representative of the human disease and good predictors of the therapeutic response in patients. In this context, great emphasis has been directed toward 3D tumor models aiming to surmount the insufficient predictive power of traditional 2D monolayer cultures of cancer cells. This review focuses on multicellular tumor spheroids (MCTS), which are currently the most widely employed 3D tumor model in preclinical studies. After a brief discussion on spheroid construction strategies and analytical/imaging techniques employed in experimental settings, the application of 3D MCTS to the evaluation of nanomedicines displaying various physico-chemical properties is reviewed. Finally, relevant examples of scaffold and microfluidic systems in which MCTS have been included are described

Involvement of Macrophages in the Pathogenesis of Transmissible Spongiform Encephalopathies

Although transmissible spongiform encephalopathies (TSE) or prion diseases are neurodegenerative disorders, the immune system is also involved, at least in the early stages of their pathogenesis. Extensive studies have focused on cells targeted by the TSE agent for its replication but few on the possible involvement of macrophages in its clearance, as in more conventional diseases. This review summarises some of the experiments aimed at demonstrating a role for macrophages in TSE and presents the application to TSE of the macrophage "suicide" technique, which has been used to clarify the implication of these cells in the early steps of TSE pathogenesis

Super Vector !

Concevoir de nouveaux systèmes pharmaceutiques, développer des nanomédicaments... porte-drapeau des nanotechnologies à usage biomédical, Patrick Couvreur revient, non sans une pointe d’humour, sur son parcours « galéniste » et sur les gélules devenues nanomédicaments

Outcome of anterior lumbar interbody fusion : a retrospective study of clinical and radiologic parameters

Objective. This study aims to critically evaluate the long-term results of stand-alone anterior lumbar interbody fusion (ALIF), without use of rhBMP-2, as a therapeutic option for symptomatic patients with degenerative disc disease (DDD). Furthermore this study intends to identify predictive parameters for anterior lumbar interbody fusion outcome. Methods. A retrospective cohort study with additional telephone interview to obtain missing data was performed. All patients who underwent a L4-L5 and/or L5-S1 ALIF-procedure in the period between 2006 and 2011 were identified. The medical files of 123 patients with 154 fusion levels were reviewed. All patients were contacted by phone to gather supplementary and missing information. Pain and functionality scores (Visual Analogue Scale [VAS] and Oswestry Disability Index [ODI]), radiological (intervertebral disc height, Modic and Pfirrmann classifications) and different clinical parameters were gathered. Results. The mean age at surgery of the population was 46.2 years. Overall, 59 female and 64 male patients were included in the study. The mean visual analogue scales (VAS) for back and leg pain improved significantly (P<0.001) with 5 and 4.4 points respectively at 3 years follow-up. Modic-type I changes are associated with a better improvement in VAS-score for back pain (P=0.026), Pfirrmann-grades IV and V and an intervertebral disc height of less than 5 mm are associated with a better improvement in leg pain (respective P-values: 0.045 and 0.033). Overall, 89% of patients would reconsider the surgical intervention. Conclusions. The ALIF-technique is a durable treatment option for patients with DDD. This study suggests different predictive parameters for treatment outcome

Adressage de Nanomédicaments à base de squalène

Les nanoparticules de Gemcitabine-Squalène (Gem-Sq), synthétisées suivant le concept de squalénisation , ont montré des activités anticancéreuses très supérieures à celles obtenues en présence de Gem libre. Néanmoins, leur PEGylation, c est-à-dire leur décoration par du poly(éthylène glycol)-squalène (PEG-Sq) pour augmenter leur temps de demi-vie plasmatique, s est avérée infructueuse du fait d une déstructuration colloïdale. Par ailleurs, aucune stratégie de fonctionnalisation pour effectuer un ciblage actif de cellules cancéreuses, n est à ce jour disponible. Au cours de cette thèse, nous avons donc cherché à résoudre ces problèmes. Après une étude bibliographique portant sur la conception de nanoparticules de prodrogues lipidiques, dans le but d établir un constat récent de l état de l art dans ce domaine, nous avons proposé une voie de synthèse pour obtenir des nanoparticules multifonctionnelles (i.e., thérapeutique, fluorescentes et ciblées) à base de Gem-Sq, et ce par co-auto-assemblage des composés conjugués de Rhodamine-Sq, Gem-Sq et Biotin-Sq. Ces nanoparticules ont montré une internalisation plus importante dans les cellules cancéreuses et une meilleure efficacité thérapeutique que les nanoparticules de Gem-Sq non-fonctionnalisées. Dans un deuxième temps, nous avons apporté une solution au problème de la PEGylation des nanoparticules de Sq via la synthèse et l utilisation de composés conjugués de type Gem-poly(méthacrylate de squalène). Ces prodrogues macromoléculaires ont été synthétisées par polymérisation radicalaire contrôlée et plus précisément par la technique RAFT. Les nanoparticules obtenues par auto-assemblage en solution aqueuse sont stables et présentent des activités anticancéreuses importantes sur différentes lignées cellulaires. Leur PEGylation par ajout de Sq-PEG durant la formulation s est avérée possible et n a pas conduit à une déstabilisation colloïdale. Enfin, j ai participé à l élaboration d une nouvelle famille de nanoparticules de prodrogues macromoléculaires qui a consisté à faire croitre de courtes chaines de polyisoprène (PI) à partir de la Gem, donnant ainsi des conjugués de type Gem-PI, capables de s auto-assembler sous la forme de nanoparticules avec une activité anticancéreuse in vitro et in vivo.Gemcitabine-Squalene (Gem-Sq) nanoparticles have been synthesized from the squalenoylation approach and have shown superior anticancer activities compared to those obtained with free Gem. However, their PEGylation, that is their coating with poly(ethylene glycol)-squalene (PEG-Sq) in order to increase their circulation time, has been unsuccessful, leading to colloidal disassembly. In addition, to the best of our knowledge, there is not functionalization strategy yet available to perform active targeting against cancer. During this PhD thesis, we have been looking for solutions to tackle these two important problems. After a littérature survey about the design of lipidic prodrug nanoparticles, in order to establish a pretty accurate picture of the domain, we have reported a synthetic approach towards multifunctional Sq-based nanoparticles (i.e., therapeutic, fluorescent and targeted), through the co-self-assembly of the different Sq-based materials; that is Rhodamine-Sq, Gem-Sq and Biotin-Sq. These nanoparticles have demonstrated a greater internalization into cancer cells and a greater therapeutic effect than non-functionalized Gem-Sq nanoparticles. In the next step, we have provided a solution to the PEGylation issue by synthetizing Gem-poly(squalenoyl methacrylate) macromolecular prodrugs. These materials have been prepared by controlled/living radical polymerization and especially the RAFT technique. The resulting nanoparticles exhibited significant anticancer activities against various cancer cells and can be successfully PEGylated by the addition of Sq-PEG during their formulation. Eventually, I have participated to the design of a new family of macromolecular prodrugs obtained from the growing of short polyisoprene (PI) chains from Gem, leading to Gem-PI nanoparticles after self-assembly of Gem-PI. The nanoparticles led to significant anticancer activity both in vitro and in vivo.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF