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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/28329446/in-vitro-intrinsic-permeability-a-transporter-independent-measure-of-caco-2-cell-permeability-in-drug-design-and-development
#1
Linda Fredlund, Susanne Winiwarter, Constanze Hilgendorf
In-vitro permeability data have a central place in absorption risk assessments in drug discovery and development. For compounds where active efflux impacts permeability in vitro, the inherent passive membrane permeability ("intrinsic permeability"), gives a concentration-independent measure of the compound's permeability. This work describes the validation of an in-vitro intrinsic permeability assay and application of the data in a predictive in-silico model. Apparent intrinsic permeability (Papp) across Caco-2 cell monolayers is determined in presence of an optimized cocktail of chemical inhibitors towards the three major efflux transporters ABCB1, ABCC2, and ABCG2...
March 22, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28329443/analyzing-the-potential-root-causes-of-variability-of-pharmacokinetics-in-preclinical-species
#2
Pierre Daublain, Kung-I Feng, Michael D Altman, Iain Martin, Suman Mukherjee, Rebecca Nofsinger, Alan B Northrup, Richard Tschirret-Guth, Mark Cartwright, Caroline McGregor
The purpose of this research was to assess variability in pharmacokinetic profiles (PK variability) in preclinical species and identify the risk factors associated with the properties of a drug molecule that contribute to the variability. Exposure data in mouse, rat, dog and monkey for a total of 16,592 research compounds studied between 1999 and 2013 were included in the analysis. Both in vivo study parameters and in silico/experimental physicochemical properties of the molecules were analyzed. Areas under the plasma concentration vs...
March 22, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28328222/correction-to-characterization-of-the-particle-size-and-polydispersity-of-dicumarol-using-solid-state-nmr-spectroscopy
#3
Kassibla Elodie Dempah, Joseph W Lubach, Eric J Munson
No abstract text is available yet for this article.
March 22, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28291364/multifunctional-nanoparticles-loading-with-docetaxel-and-gdc0941-for-reversing-multidrug-resistance-mediated-by-pi3k-akt-signal-pathway
#4
Yiyue Wang, Jing Li, Jing Jing Chen, Xuan Gao, Zun Huang, Qi Shen
The polylactic-co-glycolic acid polyethylene glycol conjugated with cell penetrating peptide R7 (PLGA-PEG-R7)/polysulfadimethoxine-folate nanoparticles loaded with docetaxel (DTX) and GDC0941 (R7/PSD-Fol NPs) were prepared to overcome multidrug resistance (MDR) and enhance the antitumor activity. First, polysulfadimethoxine-folate was synthesized to construct the R7/PSD-Fol NPs. The R7/PSD-Fol NPs were prepared with the abilities of effective entrapment and drug loading. Due to the pH-sensitive effect of PSD-folate, the releasing of DTX and GDC0941 from the R7/PSD-Fol NPs was lower in pH 7...
March 22, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28287743/a-systematic-study-of-molecular-interactions-of-anionic-drugs-with-a-dimethylaminoethyl-methacrylate-copolymer-regarding-solubility-enhancement
#5
Wiebke Saal, Alfred Ross, Nicole Wyttenbach, Jochem Alsenz, Martin Kuentz
The methacrylate-copolymer Eudragit EPO (EPO) has raised interest in solubility enhancement of anionic drugs. Effects on aqueous drug solubility at rather low polymer concentrations are barely known despite their importance upon dissolution and dilution of oral dosage forms. We provide evidence for substantial enhancement (factor 4-230) of aqueous solubility of poorly water-soluble anionic drugs induced by low (0.1-5% (w/w)) concentration of EPO for a panel of seven acidic crystalline drugs. Diffusion data (determined by (1)H nuclear magnetic resonance spectroscopy) indicate that the solubility increasing effect monitored by quantitative ultraperformance liquid chromatography was caused primarily by molecular API polymer interactions in the bulk liquid phase...
March 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28282145/targeted-ultrasound-triggered-phase-transition-nanodroplets-for-her2-overexpressing-breast-cancer-diagnosis-and-gene-transfection
#6
Di Gao, Jinbiao Gao, Ming Xu, Zhong Cao, Luyao Zhou, Yingqin Li, Xiaoyan Xie, Qing Jiang, Wei Wang, Jie Liu
For successful gene therapy, it is imperative to accumulate therapeutic gene in tumor tissues followed by efficiently delivering gene into targeted cells. Ultrasound irradiation, as a noninvasive and cost-effective external stimulus, has been proved to be one of the most potential external-stimulating gene delivery strategies recently in further improving gene transfection. In this study, we developed tumor-targeting ultrasound-triggered phase-transition nanodroplets AHNP-PFP-TNDs comprising a perfluorinated poly(amino acid) C11F17-PAsp (DET) as a core for simultaneously loading perfluoropentane (PFP) and nucleic acids, and a polyanionic polymer PGA-g-PEG-AHNP as the shell for not only modifying the surface of nanodroplets but also introducing an anti-Her2/neu peptide (AHNP) aiming to targeted treatment of Her2-overexpressing breast cancer...
March 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28263073/investigation-into-the-biological-impact-of-block-size-on-cathepsin-s-degradable-hpma-copolymers
#7
Wei Fan, Wenting Zhang, Yinnong Jia, Susan K Brusnahan, Jered C Garrison
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers have been studied as an efficient carrier for drug delivery and tumor imaging. However, as with many macromolecular platforms, the substantial accumulation of HPMA copolymer by the mononuclear phagocyte system (MPS)-associated tissues, such as the blood, liver, and spleen, has inhibited its clinical translation. Our laboratory is pursuing approaches to improve the diagnostic and radiotherapeutic effectiveness of HPMA copolymers by reducing the nontarget accumulation...
March 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28319404/encapsulation-of-an-ep67-conjugated-ctl-peptide-vaccine-in-nanoscale-biodegradable-particles-increases-the-efficacy-of-respiratory-immunization-and-affects-the-magnitude-and-memory-subsets-of-vaccine-generated-mucosal-and-systemic-cd8-t-cells-in-a-diameter
#8
Bala Vamsi Krishna Karuturi, Shailendra B Tallapaka, Pravin Yeapuri, Stephen M Curran, Sam D Sanderson, Joseph A Vetro
The diameter of biodegradable particles used to co-encapsulate immunostimulants and subunit vaccines affects the magnitude of memory CD8(+) T cells generated by systemic immunization. Possible effects on the magnitude of CD8(+) T cells generated by mucosal immunization or memory subsets that potentially correlate more strongly with protection against certain pathogens, however, are unknown. In this study, we conjugated our novel host-derived mucosal immunostimulant, EP67, to the protective MCMV CTL epitope, pp89, through a lysosomal protease-labile double arginine linker (pp89-RR-EP67) and encapsulated in PLGA 50:50 micro- or nanoparticles...
March 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28252969/in-vitro-and-in-silico-tools-to-assess-extent-of-cellular-uptake-and-lysosomal-sequestration-of-respiratory-drugs-in-human-alveolar-macrophages
#9
Ayşe Ufuk, Frauke Assmus, Laura Francis, Jonathan Plumb, Valeriu Damian, Michael Gertz, J Brian Houston, Aleksandra Galetin
Accumulation of respiratory drugs in human alveolar macrophages (AMs) has not been extensively studied in vitro and in silico despite its potential impact on therapeutic efficacy and/or occurrence of phospholipidosis. The current study aims to characterize the accumulation and subcellular distribution of drugs with respiratory indication in human AMs and to develop an in silico mechanistic AM model to predict lysosomal accumulation of investigated drugs. The data set included 9 drugs previously investigated in rat AM cell line NR8383...
March 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28300416/correction-to-prediction-of-ocular-drug-distribution-from-systemic-blood-circulation
#10
Kati-Sisko Vellonen, Esa-Matti Soini, Eva M Del Amo, Arto Urtti
No abstract text is available yet for this article.
March 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28300411/h2s-releasing-polymer-micelles-for-studying-selective-cell-toxicity
#11
Jeffrey C Foster, Scott C Radzinski, Xianlin Zou, Carla V Finkielstein, John B Matson
We report the preparation of S-aroylthiooxime (SATO) functionalized amphiphilic block copolymer micelles that release hydrogen sulfide (H2S), a gaseous signaling molecule of relevance to various physiological and pathological conditions. The micelles release H2S in response to cysteine with a half-life of 3.3 h, which is substantially slower than a related small molecule SATO. Exogenous administration of H2S impacts growth and proliferation of cancer cells; however, the limited control over H2S generation from inorganic sulfide sources results in conflicting reports...
March 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28279069/brain-and-organ-uptake-in-the-rhesus-monkey-in-vivo-of-recombinant-iduronidase-compared-to-an-insulin-receptor-antibody-iduronidase-fusion-protein
#12
Ruben J Boado, William M Pardridge
Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-l-iduronidase (IDUA), and patients with MPSI are currently treated with IDUA enzyme replacement therapy (ERT). However, the majority of MPSI patients have severe CNS involvement, and conventional ERT does not treat the brain. The failure of ERT to treat the brain is believed to be due to the lack of IDUA transport through the blood-brain barrier (BBB). However, BBB transport of IDUA has not been directly measured, to date...
March 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28257578/amelioration-of-experimental-autoimmune-encephalomyelitis-in-mice-by-interferon-beta-gene-therapy-using-a-long-term-expression-plasmid-vector
#13
Atsushi Hamana, Yuki Takahashi, Akane Tanioka, Makiya Nishikawa, Yoshinobu Takakura
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Repeated injections of the interferon-β (IFN-β) protein are required for relapse prevention therapy in patients with MS. IFN-β gene transfer can be an alternative treatment that continuously supplies IFN-β protein to the patient without requiring repeated injections. In a previous study, we constructed a novel long-term IFN-β-expressing plasmid vector (pMx-IFN-β). In the present study, we examined whether gene transfer of pMx-IFN-β could be effective for the treatment of MS in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS...
March 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28296410/a-light-responsive-nanoparticle-based-delivery-system-using-pheophorbide-a-graft-polyethyleneimine-for-dendritic-cell-based-cancer-immunotherapy
#14
Chuangnian Zhang, Ju Zhang, Gaona Shi, Huijuan Song, Shengbin Shi, Xiuyuan Zhang, Pingsheng Huang, Zhihong Wang, Weiwei Wang, Chun Wang, Deling Kong, Chen Li
In this study, the photochemical internalization (PCI) technique was adopted in a nanoparticle-based antigen delivery system to enhance antigen-specific CD8(+) T cell immune response for cancer immunotherapy. Pheophorbide-A, a hydrophobic photosensitizer, grafted with polyethyleneimine (PheoA-PEI) with endosome escape activity and near infrared imaging capability was prepared. A model antigen ovalbumin (OVA) was then complexed with PheoA-PEI to form PheoA-PEI/OVA nanoparticles (PheoA-PEI/OVA NPs) that are responsive to light...
March 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28296409/microfibrous-solid-dispersions-of-poorly-water-soluble-drugs-produced-via-centrifugal-spinning-unexpected-dissolution-behaviour-on-recrystallization
#15
Stefania Marano, Susan Anne Barker, Shahrzad Missaghi, Ali Rajabi-Siahboomi, Bahijja Tolulope Raimi-Abraham, Abil E Aliev, Duncan Q M Craig
Temperature-controlled, solvent-free centrifugal spinning may be used as a means of rapid production of amorphous solid dispersions in the form of drug-loaded sucrose microfibers. However, due to the high content of amorphous sucrose in the formulations, such microfibers may be highly hygroscopic and unstable on storage. In this study, we explore both the effects of water uptake of the microfibers and the consequences of deliberate recrystallization for the associated dissolution profiles. The stability of sucrose microfibers loaded with three selected BCS class II model drugs (itraconazole (ITZ), olanzapine (OLZ) and piroxicam (PRX)) was investigated under four different relative humidity conditions (11, 33, 53 and 75% RH) at 25°C for 8 months, particularly focusing on the effect of the highest level of moisture (75% RH) on the morphology, size, drug distribution, physical state and dissolution performance of microfibers...
March 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28294625/poly-ethyl-glyoxylate-poly-ethylene-oxide-nanoparticles-stimuli-responsive-drug-release-via-end-to-end-polyglyoxylate-depolymerization
#16
Bo Fan, Elizabeth R Gillies
The ability to disrupt polymer assemblies in response to specific stimuli provides the potential to release drugs selectively at certain sites or conditions in vivo. However, most stimuli-responsive delivery systems require many stimuli-initiated events to release drugs. "Self-immolative polymers" offer the potential to provide amplified responses to stimuli as they undergo complete end-to-end depolymerization following the cleavage of a single end-cap. Herein, linker end-caps were developed to conjugate self-immolative poly(ethyl glyoxylate) (PEtG) with poly(ethylene oxide) (PEO) to form amphiphilic block copolymers...
March 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28294623/characterization-of-the-physicochemical-properties-of-%C3%AE-cyclodextrin-divinyl-sulfone-polymer-carrier-bile-acid-systems
#17
Mohamed H Mohamed, Chen Wang, Kerry M Peru, John V Headley, Lee D Wilson
Herein, we report on the systematic design and characterization of cross-linked polymer carriers containing β-cyclodextrin (β-CD) and divinyl sulfone (DVS). The polymer carriers were prepared at variable feed ratios (β-CD-DVS; 1:1, 1:2, 1:3 and 1:6) and characterized using spectroscopy (IR, 1H solution NMR, 13C CP-MAS solids NMR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and a dye decolorization method using phenolphthalein. Uptake studies were carried out at pH 9.00 for the polymer carriers using single component bile acids (cholic acid; deoxycholic acid; glycodeoxycholic acid; and taurodeoxycholic acid)...
March 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28294622/tracking-antibody-distribution-with-near-infrared-fluorescent-dyes-impact-of-dye-structure-and-degree-of-labeling-on-plasma-clearance
#18
Cornelius Cilliers, Ian Nessler, Nikolas Christodolu, Greg M Thurber
Monoclonal antibodies labeled with near infrared (NIR) fluorophores have potential use in disease detection, intraoperative imaging, and pharmacokinetic characterization of therapeutic antibodies in both the preclinical and clinical setting. Recent work has shown conjugation of NIR fluorophores to antibodies can potentially alter antibody disposition at a sufficiently high degree of labeling (DoL); however, other reports show minimal impact after labeling with NIR fluorophores. In this work, we label two clinically approved antibodies Herceptin (trastuzumab) and Avastin (bevacizumab) with NIR dyes IRDye 800CW (800CW) or Alexa Fluor 680 (AF680), at 1...
March 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28292180/immunopet-and-near-infrared-fluorescence-imaging-of-pancreatic-cancer-with-a-dual-labeled-bispecific-antibody-fragment
#19
Haiming Luo, Christopher G England, Shreya Goel, Stephen A Graves, Fanrong Ai, Bai Liu, Charles P Theuer, Hing C Wong, Robert J Nickles, Weibo Cai
Dual-targeted imaging agents have shown improved targeting efficiencies in comparison to single-targeted entities. The purpose of this study was to quantitatively assess the tumor accumulation of a dual-labeled heterobifunctional imaging agent, targeting two overexpressed biomarkers in pancreatic cancer, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging modalities. A bispecific immunoconjugate (heterodimer) of CD105 and tissue factor (TF) Fab' antibody fragments was developed using click chemistry...
March 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28291371/activity-of-multidrug-resistance-associated-proteins-1-5-mrp1-5-in-the-rpmi-2650-cell-line-and-explants-of-human-nasal-turbinate
#20
Anne M Dolberg, Stephan Reichl
The profound influence of ATP-binding cassette (ABC) transporters on the disposition of numerous drugs has led to increased interest in characterizing their expression profiles in various epithelial and endothelial barriers. The present work examined the presence and functional activity of five ABC efflux proteins, i.e. MRP 1 - 5, in freshly isolated human nasal epithelial cells and two in vitro models based on the human RPMI 2650 cell line. To evaluate the expression patterns of MRP1, MRP2, MRP3, MRP4 and MRP5 at the mRNA and protein levels in the ex vivo model and the differently cultured RPMI 2650 cells, reverse transcriptase polymerase chain reaction (RT-PCR), Western blot analysis and indirect immunofluorescence staining were used...
March 14, 2017: Molecular Pharmaceutics
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