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https://www.readbyqxmd.com/read/28546333/microdosing-drug-development-of-small-organic-and-protein-therapeutics
#1
Mats L Bergstrom
Microdosing as a regulatory concept was introduced to facilitate explorative studies in humans, using very low doses for plasma PK assessment with highly sensitive read-out or for imaging studies with radionuclide-labelled compounds. The bearing principle was that at these low doses, with limited exposure in limited time periods and in well controlled small populations, the risk of adverse effect is low. This regulation included specifications on a reduced pre-clinical toxicity assessment package making the route to human studies more rapid and cheap...
May 25, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28544971/development-of-photostable-fluorophores-for-molecular-imaging
#2
REVIEW
Qinsi Zheng, Luke D Lavis
Advances in fluorescence microscopy promise to unlock details of biological systems with high spatiotemporal precision. These new techniques also place a heavy demand on the 'photon budget'-the number of photons one can extract from a sample. Improving the photostability of small molecule fluorophores using chemistry is a straightforward method for increasing the photon budget. Here, we review the (sometimes sparse) efforts to understand the mechanism of fluorophore photobleaching and recent advances to improve photostability through reducing the propensity for oxidation or through intramolecular triplet-state quenching...
May 22, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28544466/simultaneous-imaging-of-endogenous-survivin-mrna-and-on-demand-drug-release-in-live-cells-by-using-a-mesoporous-silica-nanoquencher
#3
Peiyan Yuan, Xin Mao, Kok Chan Chong, Jiaqi Fu, Sijun Pan, Shuizhu Wu, Changmin Yu, Shao Q Yao
The design of multifunctional drug delivery systems capable of simultaneous target detection, imaging, and therapeutics in live mammalian cells is critical for biomedical research. In this study, by using mesoporous silica nanoparticles (MSNs) chemically modified with a small-molecule dark quencher, followed by sequential drug encapsulation, MSN capping with a dye-labeled antisense oligonucleotide, and bioorthogonal surface modification with cell-penetrating poly(disulfide)s, the authors have successfully developed the first mesoporous silica nanoquencher (qMSN), characterized by high drug-loading and endocytosis-independent cell uptake, which is able to quantitatively image endogenous survivin mRNA and release the loaded drug in a manner that depends on the survivin expression level in tumor cells...
May 24, 2017: Small
https://www.readbyqxmd.com/read/28541353/pendant-chain-engineering-to-fine-tune-the-nanomorphologies-and-solid-state-luminescence-of-naphthalimide-aieegens-application-to-phenolic-nitro-explosive-detection-in-water
#4
Niranjan Meher, Parameswar Krishnan Iyer
Strategically, a series of five angular "V" shaped naphthalimide AIEEgens with varying pendant chains (butyl, hexyl, octyl, cyclohexyl and methylcyclohexyl) have been synthesized to fine-tune their nanomorphological and photophysical properties. With similar aromatic cores and electronic states, unexpected tuning of the condensed state emission colors and nanomorphologies (reproducible on any kind of surface) of naphthalimides has been achieved for the first time simply by varying their side chains. Conclusive analysis by various spectroscopic techniques (SC-XRD, powder-XRD, DLS, FESEM) and DFT computational studies confirmed the full control of the pendant chain (in terms of bulkiness around the naphthalimide core, which restricts the ease of intermolecular π-π interactions) over the nanoaggregate morphology and solid state emissive properties of the AIEEgens; this can be rationalized to all aggregation-prone systems...
May 25, 2017: Nanoscale
https://www.readbyqxmd.com/read/28540381/lipoic-acid-based-core-cross-linked-micelles-for-multivalent-platforms-design-synthesis-and-application-in-bio-imaging-and-drug-delivery
#5
Jingsheng Huang, Fang Wu, Yunlong Yu, Haolong Huang, Shiyong Zhang, Jingsong You
Natural lipoic acid derived small-molecule amphiphiles self-assemble into micelles in water. The presence of numerous disulfides accumulated in the core makes the micelles readily cross-linked to achieve the establishment of core cross-linked micelles (CCMs). Thanks to the inherent biocompatibility, the resulting lipoic acid based CCMs (LA-CCMs) are good multivalent platforms for biomedical applications.
May 25, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28537735/improved-superresolution-imaging-using-telegraph-noise-in-organic-semiconductor-nanoparticles
#6
Yifei Jiang, Muskendol Novoa, Teeranan Nongnual, Rhonda Powell, Terri F Bruce, Jason D McNeill
Small semiconductor structures often exhibit "telegraph noise". If the number of charge carriers is small, then spontaneous changes in the number of carriers can lead to abrupt switching between two or more discrete levels, leading to burst noise or popcorn noise in transistors. We have observed similar behavior in the fluorescence of organic semiconductor nanoparticles, where typical carrier populations are often less than ~10 carriers per nanoparticle. Spontaneous changes in the number of charges results in abrupt switching between 2 or more fluorescence intensity levels, since the charges act as highly efficient fluorescence quenchers...
May 24, 2017: Nano Letters
https://www.readbyqxmd.com/read/28535032/applying-thienyl-side-chains-and-different-%C3%AF-bridge-to-aromatic-side-chain-substituted-indacenodithiophene-based-small-molecule-donors-for-high-performance-organic-solar-cells
#7
Jin-Liang Wang, Kai-Kai Liu, Sha Liu, Feng Liu, Hongbin Wu, Yong Cao, Thomas P Russell
A pair of linear tetrafluorinated small molecular donors, named as ThIDTTh4F and ThIDTSe4F, which are with tetrathienyl-substituted IDT as electron-rich central core, electron-deficient difluorobenzothiadiazole as acceptor units, and donor end-capping groups, but having differences in the π-bridge (thiophene and selenophene), were successfully synthesized and evaluated as donor materials in organic solar cells. Such π-bridge and core units in these small molecules play a decisive role in the formation of the nanoscale separation of the blend films, which were systematically investigated through absorption spectra, grazing incidence X-ray diffraction pattern, transmission electron microscopy images, resonant soft X-ray scattering profiles, and charge mobility measurement...
May 23, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28534298/formulation-and-in-vitro-characterization-of-bioactive-mesoporous-silica-with-doxorubicin-and-metronidazole-intended-for-bone-treatment-and-regeneration
#8
Katarzyna Czarnobaj, Magdalena Prokopowicz, Wiesław Sawicki
The purpose of this study was to evaluate the surface mineralization activity and in vitro drug behavior potential of two forms of mesoporous silica: powder and granulate. Ordered mesoporous SiO2 powder was synthesized by surfactant-assisted sol-gel process using tetraethoxysilane as a silica precursor and hexadecyltrimethylammonium bromide as the structure-directing agent. The granulate was prepared using silica powder and ethyl cellulose as a binding agent. Metronidazole (MT)-an anti-inflammatory substance and doxorubicin hydrochloride (ChD)-an anti-cancer drug were chosen as drug models for delivery studies...
May 22, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28532118/facile-synthesis-of-polymeric-fluorescent-organic-nanoparticles-based-on-the-self-polymerization-of-dopamine-for-biological-imaging
#9
Yingge Shi, Ruming Jiang, Meiying Liu, Lihua Fu, Guangjian Zeng, Qing Wan, Liucheng Mao, Fengjie Deng, Xiaoyong Zhang, Yen Wei
Polymeric fluorescent organic nanoparticles (polymer-FONs) have raised considerable research attention for biomedical applications owing to their advantages as compared with fluorescent inorganic nanoparticles and small organic molecules. In this study, we presented an efficient, facile and environment-friendly strategy to produce polymer-FONs, which relied on the self-polymerization of dopamine and polyethyleneimine (PEI) in rather mild conditions. To obtain the final polymer-FONs, aldehyde group-containing copolymers (named as poly(UA-co-PEGMA)) were synthesized by reversible addition-fragmentation chain-transfer polymerization using polyethylene glycol methyl ether methacrylate (PEGMA) and 1-undecen-10-al (UA) as monomers...
August 1, 2017: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/28531986/biomimicking-synthesis-of-photoluminescent-molecular-lantern-catalyzed-by-in-situ-formation-of-nanogold-catalysts
#10
Yong Yu, Xin Ting Zheng, Boon Wei Yee, Yen Nee Tan
Bioluminescence has been widely recognized as a powerful imaging tool for biological investigations. Synthesis of molecular lanterns that mimic bioluminescence in nature is of great interest. Herein we report a synthesis of molecular lantern by utilizing the catalytic properties of ultrasmall (<2nm) gold nanoclusters (AuNC), which is inspired by the enzymatic light-up of luciferin in the biological system. Small molecules such as hydroquinone and Cys-Gly peptides are used to direct the synthesis of AuNC via a biotemplating approach, while the in-situ formation of AuNC simultaneously catalyze the formation of luciferin-like, brightly fluorescent dye (λem=520nm, QY=0...
August 1, 2017: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/28530802/discovery-of-n-5-fluoropyridin-2-yl-6-methyl-4-pyrimidin-5-yloxy-picolinamide-vu0424238-a-novel-negative-allosteric-modulator-of-metabotropic-glutamate-receptor-subtype-5-selected-for-clinical-evaluation
#11
Andrew S Felts, Alice L Rodriguez, Anna L Blobaum, Ryan D Morrison, Brittney S Bates, Analisa Thompson Gray, Jerri M Rook, Mohammed N Tantawy, Frank W Byers, Sichen Chang, Daryl F Venable, Vincent B Luscombe, Gilles D Tamagnan, Colleen M Niswender, J Scott Daniels, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley, Kyle A Emmitte
Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28530285/one-step-formulation-of-nonionic-surfactant-bicelles-nsbs-by-a-double-tailed-polyglycerol-type-nonionic-surfactant
#12
Kenji Aramaki, Chikahiro Iwata, Jitendra Mata, Tetsuya Maehara, Daisuke Aburano, Yuichi Sakanishi, Kyuhei Kitao
Bicelles are generally formed by phospholipid-based systems and are useful for various applications, such as nanocarriers or membrane protein crystallization. The same disc-like assemblies, nonionic surfactant bicelles (NSBs), can also be formed using nonionic amphiphiles, but this has not been reported extensively. We report a novel NSB system that employs the double-tailed nonionic amphiphile, polyglyceryl dialkyl ether (C12CmGn), which has two alkyl chains and a polyglyceryl group. A symmetric-tail molecule, C12C12G13...
May 22, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28530280/visualization-of-vesicular-transport-from-the-endoplasmic-reticulum-to-lysosome-using-an-amidine-derived-two-photon-probe
#13
Hyo Won Lee, Myoung Ki Cho, Hye-Ri Kim, Chang Su Lim, Chulhun Kang, Hwan Myung Kim
We report an amidine-based small molecule two-photon fluorescent probe (ELP1) for monitoring vesicle transport from the ER to lysosome in live cells. Two-photon microscopy imaging studies indicated that this probe initially localized in the ER and subsequently transferred to lysosomal compartments through vesicular transport. These results may provide an effective tool for studying trafficking-related biology and pathology in real-time.
May 22, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28528635/relocation-is-the-key-to-successful-correlative-fluorescence-and-scanning-electron-microscopy
#14
Delfine Cheng, Gerald Shami, Marco Morsch, Minh Huynh, Patrick Trimby, Filip Braet
In this chapter the authors report on an automated hardware and software solution enabling swift correlative sample array mapping of fluorescently stained molecules within cells and tissues across length scales. Samples are first observed utilizing wide-field optical and fluorescence microscopy, followed by scanning electron microscopy, using calibration points on a dedicated sample-relocation holder. We investigated HeLa cells in vitro, fluorescently labeled for monosialoganglioside one (GM-1), across both imaging platforms within tens of minutes of initial sample preparation...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28525955/imaging-and-manipulating-energy-transfer-among-quantum-dots-at-individual-dot-resolution
#15
Duc A Nguyen, Huy A Nguyen, Joseph W Lyding, Martin Gruebele
Many processes of interest in quantum dots involve charge or energy transfer from one dot to another. Energy transfer in films of quantum dots as well as between linked quantum dots has been demonstrated by luminescence shift, and the ultrafast time-dependence of energy transfer processes has been resolved. Bandgap variation among dots (energy disorder) and dot separation are known to play an important role in how energy diffuses. Thus it would be very useful if energy transfer could be visualized directly on a dot-by-dot basis among small clusters or within films of quantum dots...
May 19, 2017: ACS Nano
https://www.readbyqxmd.com/read/28524652/optical-characteristics-and-tumor-imaging-capabilities-of-near-infrared-dyes-in-free-and-nano-encapsulated-formulations-comprised-of-viral-capsids
#16
Yadir Guerrero, Sheela Singh, Turong Mai, Ravoori Murali, Leela Tanikella, Atta Zahedi, Vikas Kundra, Bahman Anvari
Near infrared (NIR) fluorescent molecules and nano-sized structures can serve as potential optical probes for image-guided removal of small tumor nodules (≈ < 1 mm diameter). While indocyanine green (ICG) remains as the only FDA-approved NIR dye, other organic dyes are under extensive development for enhanced imaging capabilities. One such dye is BrCy106-NHS where bromine is substituted for aromatic structures in cyanine dyes. Herein, we investigate the absorption and fluorescence characteristics of ICG and BrCy106-NHS, and quantitatively assess their tumor imaging capabilities in free (non-encapsulated) and a nano-encapsulated form that utilizes the capsid protein (CP) from genome-depleted plant-infecting brome mosaic virus as the encapsulating shell...
May 19, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28524354/an-aggregating-amphiphilic-squaraine-a-light-up-probe-that-discriminates-parallel-g-quadruplexes
#17
Vincenzo Grande, Filippo Doria, Mauro Freccero, Frank Würthner
G-quadruplexes (G4s) are peculiar DNA or RNA tertiary structures that are involved in the regulation of many biological events within mammalian cells, bacteria, and viruses. Although their role as versatile therapeutic targets has been emphasized for 35 years, G4 selectivity over ubiquitous double-stranded DNA/RNA, as well as G4 differentiation by small molecules, still remains challenging. Here, a new amphiphilic dicyanovinyl-substituted squaraine, SQgl, is reported to act as an NIR fluorescent light-up probe discriminating an extensive panel of parallel G4s while it is non-fluorescent in the aggregated state...
May 19, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28523508/rodent-whole-body-sectioning-and-maldi-mass-spectrometry-imaging
#18
Paul J Trim
Here, we describe a method for obtaining whole-body MALDI imaging data. MALDI imaging provides chemical compound-specific information not attainable with conventional histology techniques. The specificity of mass spectrometry with the addition of spatial information makes this a very powerful technique, especially for the analysis of endogenous and exogenous small molecules. This chapter will provide the reader with a comprehensive description of the techniques involved in obtaining high-quality MALDI mass spectrometry imaging (MSI) data from large tissue sections...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28522808/plasmonics-enhanced-smartphone-fluorescence-microscopy
#19
Qingshan Wei, Guillermo Acuna, Seungkyeum Kim, Carolin Vietz, Derek Tseng, Jongjae Chae, Daniel Shir, Wei Luo, Philip Tinnefeld, Aydogan Ozcan
Smartphone fluorescence microscopy has various applications in point-of-care (POC) testing and diagnostics, ranging from e.g., quantification of immunoassays, detection of microorganisms, to sensing of viruses. An important need in smartphone-based microscopy and sensing techniques is to improve the detection sensitivity to enable quantification of extremely low concentrations of target molecules. Here, we demonstrate a general strategy to enhance the detection sensitivity of a smartphone-based fluorescence microscope by using surface-enhanced fluorescence (SEF) created by a thin metal-film...
May 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28522739/imaging-macrophage-accumulation-in-a-murine-model-of-chronic-pancreatitis-with-125-i-iododpa-spect-ct
#20
Catherine A Foss, Liansheng Liu, Ronnie C Mease, Haofan Wang, Pankaj Pasricha, Martin G Pomper
Background and Aims: Pancreatitis remains a diagnostic challenge in patients with mild to moderate disease, with current imaging modalities inadequate. Given the prominent macrophage infiltrate in chronic pancreatitis, we hypothesized that (125)I-iodo-DPA-713 (iodoDPA), a small-molecule radiotracer that specifically targets macrophages, could be used with single photon emission computed tomography-computed tomography (SPECT-CT) to image pancreatic inflammation in a relevant experimental model. Methods: Chronic pancreatitis was induced in C57BL/6 mice with cerulein and were contrasted with vehicle-injected controls...
May 18, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
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