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131.
Alyssa B. Sanders Jacob T. Zangaro Nakoa K. Webber Ryan P. Calhoun Elizabeth A. Richards Samuel L. Ricci Hannah M. Work Daniel D. Yang Kaitlyn R. Casey Joseph C. Iovine Gabriela Baker Taylor V. Douglas Sierra B. Dutko Thomas J. Fasano Sarah A. Lofland Ashley A. Rajan Mihaela A. Vasile Benjamin R. Carone Nathaniel V. Nucci 《Molecules (Basel, Switzerland)》2022,27(5)
Despite considerable advances in recent years, challenges in delivery and storage of biological drugs persist and may delay or prohibit their clinical application. Though nanoparticle-based approaches for small molecule drug encapsulation are mature, encapsulation of proteins remains problematic due to destabilization of the protein. Reverse micelles composed of decylmonoacyl glycerol (10MAG) and lauryldimethylamino-N-oxide (LDAO) in low-viscosity alkanes have been shown to preserve the structure and stability of a wide range of biological macromolecules. Here, we present a first step on developing this system as a future platform for storage and delivery of biological drugs by replacing the non-biocompatible alkane solvent with solvents currently used in small molecule delivery systems. Using a novel screening approach, we performed a comprehensive evaluation of the 10MAG/LDAO system using two preparation methods across seven biocompatible solvents with analysis of toxicity and encapsulation efficiency for each solvent. By using an inexpensive hydrophilic small molecule to test a wide range of conditions, we identify optimal solvent properties for further development. We validate the predictions from this screen with preliminary protein encapsulation tests. The insight provided lays the foundation for further development of this system toward long-term room-temperature storage of biologics or toward water-in-oil-in-water biologic delivery systems. 相似文献
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Isabel V. L. Wilkinson Kelly J. Perkins Hannah Dugdale Lee Moir Aini Vuorinen Maria Chatzopoulou Sarah E. Squire Sebastian Monecke Alexander Lomow Marcus Geese Philip D. Charles Peter Burch Jonathan M. Tinsley Graham M. Wynne Stephen G. Davies Francis X. Wilson Fraydoon Rastinejad Shabaz Mohammed Kay E. Davies Angela J. Russell 《Angewandte Chemie (International ed. in English)》2020,59(6):2420-2428
Duchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disease arising from mutations in the dystrophin gene. Upregulation of utrophin to compensate for the missing dystrophin offers a potential therapy independent of patient genotype. The first‐in‐class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial. Promising efficacy and evidence of target engagement was observed in DMD patients after 24 weeks of treatment, however trial endpoints were not met after 48 weeks. The objective of this study was to understand the mechanism of action of ezutromid which could explain the lack of sustained efficacy and help development of new generations of utrophin modulators. Using chemical proteomics and phenotypic profiling we show that the aryl hydrocarbon receptor (AhR) is a target of ezutromid. Several lines of evidence demonstrate that ezutromid binds AhR with an apparent KD of 50 nm and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies. 相似文献
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Dr. Tao Liu Dr. Aline Nonat Dr. Maryline Beyler Dr. Martín Regueiro‐Figueroa Dr. Katia Nchimi Nono Dr. Olivier Jeannin Dr. Franck Camerel Dr. François Debaene Dr. Sarah Cianférani‐Sanglier Prof. Raphaël Tripier Dr. Carlos Platas‐Iglesias Dr. Loïc J. Charbonnière 《Angewandte Chemie (International ed. in English)》2014,53(28):7259-7263
Lanthanide complexes (Ln=Eu, Tb, and Yb) that are based on a C2‐symmetric cyclen scaffold were prepared and characterized. The addition of fluoride anions to aqueous solutions of the complexes resulted in the formation of dinuclear supramolecular compounds in which the anion is confined into the cavity that is formed by the two complexes. The supramolecular assembly process was monitored by UV/Vis absorption, luminescence, and NMR spectroscopy and high‐resolution mass spectrometry. The X‐ray crystal structure of the europium dimer revealed that the architecture of the scaffold is stabilized by synergistic effects of the Eu? F? Eu bridging motive, π stacking interactions, and a four‐component hydrogen‐bonding network, which control the assembly of the two [EuL] entities around the fluoride ion. The strong association in water allowed for the luminescence sensing of fluoride down to a detection limit of 24 nM . 相似文献
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Thode A Mellinger DK Stienessen S Martinez A Mullin K 《The Journal of the Acoustical Society of America》2002,112(1):308-321
Three-dimensional dive trajectories of three sperm whales in the Gulf of Mexico have been obtained by measuring the relative arrival times and bearings of the animals' acoustic multipath reflections, using two elements of a towed hydrophone array deployed at an unknown depth and orientation. Within the first 6-12 min of the start of a dive, the intervals between successive "clicks" of all three whales corresponded closely with the two-way travel time of an acoustic pulse traveling vertically between the animals' position and the ocean bottom. The click spectra contained multiple peaks, including a faint band of energy originally centered near 10 kHz. As the animals descended over 500 m in depth, the center frequency of this band shifted to nearly 15 kHz, but subsequently remained near this value during the rest of the dive. This frequency shift is consistent with that expected from energy scattering from an ensemble of incompressible small-scale air-filled resonators, with diameters on the order of 4 mm. One possible candidate for such an ensemble is proposed to reside in the collapsed frontal sac of the animal. A comparison of the received levels for the bottom and direct multipath arrivals indicates that the whales' acoustic directivity must range between 10-30 dB in the 5-20-kHz region. 相似文献