Tunable length of cyclic peptide–polymer conjugate self-assemblies in water

Polymers conjugated to cyclic peptides capable of forming strong hydrogen bonds can self-assemble into supramolecular bottlebrushes even in aqueous solutions. However, controlling the aggregation of these supramolecular assemblies remains an obstacle that is yet to be overcome. By introducing pH-responsive poly(dimethylamino ethyl methacrylate) (pDMAEMA) arms, the repulsive forces were tuned by adjusting the degree of protonation on the polymer arms. Neutron scattering experiments demonstrated that conjugates in an uncharged state will self-assemble into supramolecular bottlebrushes. Reducing the pH in the system led to a decrease in the number of aggregation, which was reversible by addition of base. Potentiometric titration showed a correlation between the number of aggregation and the degree of ionization of the pDMAEMA arms. Hence, a balance between the strength of the hydrogen bonds and the repulsive electrostatic interactions determines the number of aggregation and extent of self-assembly. The presented work demonstrates that conjugate self-association can be controlled by tuning the charge density on the conjugated polymer arms, paving the way for the use of responsive cyclic peptide conjugates in pharmaceutical applications

Cyclic peptide-poly(HPMA) nanotubes as drug delivery vectors : in vitro assessment, pharmacokinetics and biodistribution

Size and shape have progressively appeared as some of the key factors influencing the properties of nanosized drug delivery systems. In particular, elongated materials are thought to interact differently with cells and therefore may allow alterations of in vivo fate without changes in chemical composition. A challenge, however, remains the creation of stable self-assembled materials with anisotropic shape for delivery applications that still feature the ability to disassemble, avoiding organ accumulation and facilitating clearance from the system. In this context, we report on cyclic peptide-polymer conjugates that self-assemble into supramolecular nanotubes, as confirmed by SANS and SLS. Their behaviour ex and in vivo was studied: the nanostructures are non-toxic up to a concentration of 0.5 g L and cell uptake studies revealed that the pathway of entry was energy-dependent. Pharmacokinetic studies following intravenous injection of the peptide-polymer conjugates and a control polymer to rats showed that the larger size of the nanotubes formed by the conjugates reduced renal clearance and elongated systemic circulation. Importantly, the ability to slowly disassemble into small units allowed effective clearance of the conjugates and reduced organ accumulation, making these materials interesting candidates in the search for effective drug carriers

Effects of Time of Day and Sleep Deprivation on Motorcycle-Driving Performance

The aim of this study was to investigate whether motorcycle handling capabilities – measured by means of the efficiency of emergency manoeuvres – were dependent on prior sleep deprivation and time of day. Twelve male participants voluntarily took part in four test sessions, starting at 6 a.m., 10 a.m., 2 p.m., and 6 p.m., following a night either with or without sleep. Each test session comprised temperature and sleepiness measurements, before three different types of motorcycling tests were initiated: (1) stability in straight ahead riding at low speed (in “slow motion” mode and in “brakes and clutch” mode), (2) emergency braking and (3) crash avoidance tasks performed at 20 kph and 40 kph. The results indicate that motorcycle control at low speed depends on time of day, with an improvement in performance throughout the day. Emergency braking performance is affected at both speeds by time of day, with poorer performance (longer total stopping distance, reaction time and braking distance) in the morning, and also by sleep deprivation, from measurements obtained at 40 kph (incorrect initial speed). Except for a tendency observed after the sleepless night to deviate from the initial speed, it seems that crash avoidance capabilities are quite unaffected by the two disturbance factors. Consequently, some motorcycle handling capabilities (stability at low speed and emergency braking) change in the same way as the diurnal fluctuation observed in body temperature and sleepiness, whereas for others (crash avoidance) the participants were able to maintain their initial performance level despite the high levels of sleepiness recorded after a sleepless night. Motorcycle riders have to be aware that their handling capabilities are limited in the early morning and/or after sleep deprivation. Both these situations can increase the risk of falls and of being involved in a road accident

Tomographie par émission de positons (TEP) pour la radiothérapie : technique et innovations

International audienceL’imagerie multimodale est devenue un standard pour la planification de la radiothérapie via l’imagerie par résonance magnétique (IRM) ou la tomographie par émission de positrons (TEP) dans de nombreux cancers. Toutefois son utilisation est maintenant ancienne, et son impact a peu été rediscuté à la vue des améliorations technologiques de l’imagerie et des progrès de la radiothérapie. En TEP, nous sommes pourtant passés en 20 ans d’une imagerie fonctionnelle exclusive à une imagerie hybride (fonctionnelle et anatomique) pour laquelle les améliorations successives (temps de vol, modifications des détecteurs, numérisation, etc.) ont permis de passer d’une résolution centimétrique à actuellement 3 à 4 mm. Cet article fera le point spécifiquement sur la technologie TEP, ses dernières avancées et l’impact potentiel en radiothérapie notamment ORL

pH-Responsive, Amphiphilic Core–Shell Supramolecular Polymer Brushes from Cyclic Peptide–Polymer Conjugates

The synthesis and self-assembly of pH-responsive, amphiphilic cyclic peptide–polymer conjugates are described. The design relies on the introduction of a poly­(2-(diisopropylamino)­ethyl methacrylate) (pDPA) block between the cyclic peptide and a hydrophilic block. These conjugates are disassembled and protonated at low pH but assemble into core–shell nanotubes at physiological pH, as determined by a combination of titration experiments and scattering techniques

Radiothérapie des cancers épidermoïdes métastatiques de la tête et du cou synchrones ou métachrones oligométastatiques

International audienceHead and neck carcinomas are initially metastatic in about 15% of cases. Radiotherapy is a cornerstone in the multimodal strategy at the locoregional phase. In patients with head and neck cancer, often heav-ily pretreated and with comorbidities, who relapse locoregionally or at distant sites, radiotherapy has also become increasingly important at the metastatic phase. Data on the optimal sequence of systemic treatments and metastasis-directed treatments including stereotactic irradiation are still lacking. Several randomized head and neck trials have been initiated that should provide important answers, including one recent GORTEC trial.Les carcinomes de la tête et du cou sont métastatiques d’emblée dans environ 15 % des cas. Chez ces patients souvent lourdement traités et atteints de comorbidité, la radiothérapie est une pierre angulaire de la stratégie multimodale, tant en phase locorégionale qu’en phase métastatique. Les données sur la séquence optimale des traitements et le rôle de l’irradiation stéréotaxique font encore défaut. Plusieurs essais randomisés sur les cancers de la tête et le cou ont été mis en place et devraient apporter des éléments de réponse, dont un essai récemment terminé du GORTEC

A Comparative Analysis of Motorcycle Attitude Estimation in a Trajectory Reconstruction Framework

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Lever Arm Compensation for a Motorcycle Trajectory Reconstruction System

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Cyclic peptide–polymer nanotubes as efficient and highly potent drug delivery systems for organometallic anticancer complexes

Background and Purpose Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. Experimental Approach Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model. Key Results Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro Nav1.5 block (3–7%) and Cav1.2 binding (13–21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3–4.6% and PR 2.3–10%), suggesting that worst-case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data. Conclusion and Implications Small changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non–arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies