Layer-by-Layer Supramolecular Assemblies Based on Linear and Star-Shaped Poly(glycerol Methacrylate)s for Doxorubicin Delivery.

Layer-by-layer supramolecular assemblies based on linear and star-shaped poly(glycerol methacrylate)s for doxorubicin delivery.

Filed under: Drug and Alcohol Rehabilitation

J Biomed Mater Res A. 2012 Dec 22;
Sun Y, Gao H, Yang YW, Wang A, Wu G, Wang Y, Fan Y, Ma J

Hollow microcapsules, composed of pH responsive polyelectrolytes via a layer-by-layer (LBL) adsorption technique, were prepared. Linear or star-shaped poly(glycerol metha crylate)s (PGOHMAs) modified with 1,4-butanediamine and 1,2-ethanediamine (EDA) were synthesized and used as polycations. Poly(acrylic acid) was employed as polyanion and SiO(2) (about 170 nm) as template. After LBL absorption, SiO(2) cores were removed by HF treatment. The particle size and zeta potential were measured by dynamic light scattering, showing that the diameter of star-shaped amino-PGOHMA was larger than linear counterpart. The LBL assembly and core-etching process were evidenced by scanning electron microscope, transmission electron microscope, and energy dispersive spectrometer. The cytotoxicity experiments on human umbilical vein endothelial cells were carried out to evaluate the toxicity of LBL assembly. The star-shaped and EDA-modified PGOHMA exhibited better cell viability. The microcapsules were then used to load an anticancer drug, doxorubicin hydrochloride. High loading capacity (about 42%) and entrapment efficiency (84%) were obtained for star-shaped polymer-based microcapsules. The cumulative release rate was evaluated in vitro, showing faster release at an acidic condition compared to neutral pH. Confocal laser scanning microscopy evidenced the successful cellular uptake of DOX-loaded microparticles. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012.
HubMed – drug

Early interneuron dysfunction in ALS: Insights from a mutant sod1 zebrafish model.

Filed under: Drug and Alcohol Rehabilitation

Ann Neurol. 2012 Oct 1;
McGown A, McDearmid JR, Panagiotaki N, Tong H, Al Mashhadi S, Redhead N, Lyon AN, Beattie CE, Shaw PJ, Ramesh TM

OBJECTIVE: To determine, when, how, and which neurons initiate the onset of pathophysiology in amyotrophic lateral sclerosis (ALS) using a transgenic mutant sod1 zebrafish model and identify neuroprotective drugs. METHODS: Proteinopathies such as ALS involve mutant proteins that misfold and activate the heat shock stress response (HSR). The HSR is indicative of neuronal stress, and we used a fluorescent hsp70-DsRed reporter in our transgenic zebrafish to track neuronal stress and to measure functional changes in neurons and muscle over the course of the disease. RESULTS: We show that mutant sod1 fish first exhibited the HSR in glycinergic interneurons at 24 hours postfertilization (hpf). By 96 hpf, we observed a significant reduction in spontaneous glycinergic currents induced in spinal motor neurons. The loss of inhibition was followed by increased stress in the motor neurons of symptomatic adults and concurrent morphological changes at the neuromuscular junction (NMJ) indicative of denervation. Riluzole, the only approved ALS drug and apomorphine, an NRF2 activator, reduced the observed early neuronal stress response. INTERPRETATION: The earliest event in the pathophysiology of ALS in the mutant sod1 zebrafish model involves neuronal stress in inhibitory interneurons, resulting from mutant Sod1 expression. This is followed by a reduction in inhibitory input to motor neurons. The loss of inhibitory input may contribute to the later development of neuronal stress in motor neurons and concurrent inability to maintain the NMJ. Riluzole, the approved drug for use in ALS, modulates neuronal stress in interneurons, indicating a novel mechanism of riluzole action. ANN NEUROL 2011.
HubMed – drug

High-throughput liquid chromatography/mass spectrometry method for the quantitation of small molecules using accurate mass technologies in supporting discovery drug screening.

Filed under: Drug and Alcohol Rehabilitation

Rapid Commun Mass Spectrom. 2013 Feb 15; 27(3): 401-8
Ding X, Ghobarah H, Zhang X, Jaochico A, Liu X, Deshmukh G, Liederer BM, Hop CE, Dean B

Drug discovery samples are routinely analyzed using liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods on triple quadrupole mass spectrometers employing multiple reaction monitoring (MRM). In order to improve analysis throughput, quantitation of small molecules on a quadrupole time-of-flight (QqTOF) instrument using TOF scan and high-resolution MRM (MRM-HR) modes was evaluated in this study.Cassette dosed plasma and brain samples from nine compounds were extracted using a protein precipitation method. Separation was achieved by reversed-phase liquid chromatography. Mass spectrometric analysis was performed using TOF scan and high-resolution MRM approaches on a QqTOF mass spectrometer with turbo-ionspray ionization. Results were compared to those obtained on a triple quadrupole mass spectrometer.The dynamic range varied depending on compounds and instruments and was similar between the MRM on QqQ and full TOF scan mode on QqTOF. Linear or quadratic regression and 1/x(2) weighting were used. Resolution on the QqTOF instrument was around 32000 and mass accuracy was within 4.4?ppm. The MRM-HR method showed better sensitivity compared to the TOF scan method, and was comparable to the MRM on a QqQ mass spectrometer. Assay accuracy was within ±25%.A TOF scan method allowed the use of the generic method without compound-specific optimization and was an alternative choice for routine high-throughput quantitation of small molecules. The MRM-HR method on the QqTOF showed good sensitivity which was comparable to that obtained by the MRM method on the triple quadrupole mass spectrometer. Copyright © 2012 John Wiley & Sons, Ltd.
HubMed – drug

Design, Synthesis, and Evaluation of Bioactive Small Molecules.

Filed under: Drug and Alcohol Rehabilitation

Chem Rec. 2012 Dec 20;
Hua DH

Collaborative research projects between chemists, biologists, and medical scientists have inevitably produced many useful drugs, biosensors, and medical instrumentation. Organic chemistry lies at the heart of drug discovery and development. The current range of organic synthetic methodologies allows for the construction of unlimited libraries of small organic molecules for drug screening. In translational research projects, we have focused on the discovery of lead compounds for three major diseases: Alzheimer’s disease (AD), breast cancer, and viral infections. In the AD project, we have taken a rational-design approach and synthesized a new class of tricyclic pyrone (TP) compounds that preserve memory and motor functions in amyloid precursor protein (APP)/presenilin-1 (PS1) mice. TPs could protect neuronal death through several possible mechanisms, including their ability to inhibit the formation of both intraneuronal and extracellular amyloid ? (A?) aggregates, to increase cholesterol efflux, to restore axonal trafficking, and to enhance long-term potentiation (LTP) and restored LTP following treatment with A? oligomers. We have also synthesized a new class of gap-junction enhancers, based on substituted quinolines, that possess potent inhibitory activities against breast-cancer cells in vitro and in vivo. Although various antiviral drugs are available, the emergence of viral resistance to existing antiviral drugs and various understudied viral infections, such as norovirus and rotavirus, emphasizes the demand for the development of new antiviral agents against such infections and others. Our laboratories have undertaken these projects for the discovery of new antiviral inhibitors. The discussion of these aforementioned projects may shed light on the future development of drug candidates in the fields of AD, cancer, and viral infections. DOI 10.1002/tcr.201200016.
HubMed – drug

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