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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/28234487/effects-of-membrane-pegylation-on-entry-and-location-of-antifungal-drug-itraconazole-and-their-pharmacological-implications
#1
Monika Ewa Dzieciuch-Rojek, Chetan Poojari, Jan Bednar, Alex Bunker, Bartłomiej Kozik, Maria Nowakowska, Ilpo Vattulainen, Pawel Wydro, Mariusz Kepczynski, Tomasz Rog
Itraconazole (ITZ) is an antifungal agent used clinically to treat mycotic infections. However, its therapeutic effects are limited by low solubility in aqueous media. Liposome-based delivery systems (LDS) have been proposed as a delivery mechanism for ITZ to solve this problem. Further, PEGylation, the inclusion in the formulation of a protective "stealth sheath" of poly(ethylene glycol) around carrier particles is widely used to increase the circulation time in the bloodstream, and hence efficacy. Together, these themes underlie the importance to strengthen our mechanistic and structural understanding of ITZ incorporation into liposomes both with and without PEGylation, since it can provide a potential foundation for the rational design of LDS-based systems for the delivery of ITZ, using alternate protective polymers or formulations...
February 24, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28231007/molecular-dynamics-recrystallization-behavior-and-water-solubility-of-amorphous-anticancer-agent-bicalutamide-and-its-polyvinylpyrrolidone-mixtures
#2
Justyna Szczurek, Marzena Rams-Baron, Justyna Knapik-Kowalczuk, Agata Antosik, Joanna Szafraniec, Witold Jamroz, Mateusz Dulski, Renata Jachowicz, Marian Paluch
In this paper, we investigated the molecular mobility and physical stability of amorphous bicalutamide, a poorly water-soluble drug widely used in prostate cancer treatment. Our broadband dielectric spectroscopy measurements and differential scanning calorimetry studies revealed that amorphous BIC is a moderately fragile material with strong tendency to recrystallize from amorphous state. However, mixing the drug with polymer polyvinylpyrrolidone results in a substantial improvement of physical stability attributed to antiplasticizing effect governing by polymer additive...
February 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28231003/utilization-of-gastrointestinal-simulator-gis-an-in-vivo-predictive-dissolution-methodology-coupled-with-computational-approach-to-forecast-oral-absorption-of-dipyridamole
#3
Kazuki Matsui, Yasuhiro Tsume, Susumu Takeuchi, Amanda Searls, Gordon L Amidon
Weakly basic drugs exhibit a pH-dependent dissolution profile in the gastrointestinal (GI) tract, making it difficult to predict their oral absorption profile. The aim of this study was to investigate the utility of the Gastrointestinal Simulator (GIS), a novel in vivo predictive dissolution (iPD) methodology, in predicting the in vivo behavior of the weakly basic drug, dipyridamole, when coupled with in silico analysis. The GIS is a multi-compartmental dissolution apparatus, which represents physiological gastric emptying in the fasted state...
February 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28199124/tempo-spatial-activation-of-sequential-quadruple-stimuli-for-high-gene-expression-of-polymeric-gene-nanocomplexes
#4
Hana Cho, Young-Woo Cho, Sun-Woong Kang, Mi-Kyoung Kwak, Kang Moo Huh, You Han Bae, Han Chang Kang
The clinical application of intracellular gene delivery via nanosized carriers is hindered by intracellular multistep barriers that limit high levels of gene expression. To solve these issues, four different intracellular or external stimuli that can efficiently activate a gene carrier, a gene, or a photosensitizer (pheophorbide A [PhA]) were assessed in this study. The designed nanosized polymeric gene complexes were composed of PhA-loaded thiol-degradable polycation (PhA@RPC) and cytomegalovirus (CMV) promoter-equipped pDNA...
February 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28182434/a-model-based-approach-to-assessing-the-importance-of-intracellular-binding-sites-in-doxorubicin-disposition
#5
Ilse R Dubbelboer, Elsa Lilienberg, Erik Sjögren, Hans Lennernäs
Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (Kp,t), could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model...
February 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28199114/curcumin-loaded-blood-stable-polymeric-micelles-for-enhancing-therapeutic-effect-on-erythroleukemia
#6
Feirong Gong, Dan Chen, Xin Teng, Junhua Ge, Xianfeng Ning, Ya-Ling Shen, Jian Li, Shanfeng Wang
Curcumin has high potential in suppressing many types of cancer and overcoming multidrug resistance in a multifaceted manner by targeting diverse molecular targets. However, the rather low systemic bioavailability resulted from its poor solubility in water and fast metabolism/excretion in vivo has hampered its applications in cancer therapy. To increase the aqueous solubility of curcumin while retaining the stability in blood circulation, here we report curcumin-loaded copolymer micelles with excellent in vitro and in vivo stability and antitumor efficacy...
February 22, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28221813/transport-glucuronidation-classification-system-and-pbpk-modeling-new-approach-to-predict-the-impact-of-transporters-on-disposition-of-glucuronides
#7
Shufan Ge, Yingjie Wei, Taijun Yin, Beibei Xu, Song Gao, Ming Hu
Glucuronide metabolites require the action of efflux transporters to exit cells due to their hydrophilic properties. In this study, we proposed a transport-glucuronidation classification system and developed a PBPK model to predict the impact of BCRP on systemic exposure of glucuronides. The clearance by UGTs in S9 fractions and the efflux clearance of glucuronides by BCRP in human UGT1A9-overexpressing HeLa cells were incorporated in the classification system and PBPK model. Based on simulations for glucuronide AUC for theoretical compounds in the classification system, it was indicated that BCRP was more important for compounds with greater efflux clearance of their glucuronides by BCRP regardless of differences in clearance by UGTs...
February 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28221800/self-associating-poly-ethylene-oxide-block-poly-%C3%AE%C2%B5-caprolactone-peo-b-pcl-drug-conjugates-for-the-delivery-of-stat3-inhibitor-jsi-124-potential-application-in-cancer-immunotherapy
#8
Shyam M Garg, Mohammad Reza Vakili, Ommoleila Molavi, Afsaneh Lavasanifar
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) in tumor cells and tumor associated dendritic cells (DCs) plays a major role in the progression of cancer. JSI-124 (Cucurbitacin I) is a potent inhibitor of STAT3, however, its poor solubility and non-specificity limits its effectiveness in cancer immunotherapy. In order to achieve a nano-carrier for solubilisation and passive targeting of JSI-124 to tumor cells and tumor associated DCs, the drug was chemically conjugated to pendent COOH groups of self-associating poly(ethylene oxide)-block-poly(-carboxylate-ε-caprolactone) (PEO-b-PCCL)...
February 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28221043/radiolabeled-111-in-fgf-2-is-suitable-for-in-vitro-ex-vivo-evaluations-and-in-vivo-imaging
#9
Alessandra Moscaroli, Gabriel Jones, Tessa Lühmann, Lorenz Meinel, Stephanie Wälti, Alain Blanc, Eliane Fischer, Manuel Hilbert, Roger Schibli, Martin Béhé
Fibroblast growth factor-2 (FGF-2) is a potent modulator of cell growth and regulation, with improper FGF-2 signaling being involved in impaired responses to injury or even cancer. Therefore, the exploitation of FGF-2 as a therapeutic drives the prerequisite for effective insight into drug disposition kinetics. In this article, we present an (111)In-radiolabeled FGF-2 derivative for noninvasive imaging in small animals deploying single photon emission tomography (SPECT). (111)In-FGF-2 is equally well suitable for in vitro and ex vivo investigations as (125)I-FGF-2...
February 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28212490/vitamin-e-succinate-grafted-chitosan-oligosaccharide-rgd-conjugated-tpgs-mixed-micelles-loaded-with-paclitaxel-for-u87mg-tumor-therapy
#10
Yanzuo Chen, Shu Feng, Wenchao Liu, Zeting Yuan, Peihao Yin, Feng Gao
The poor therapeutic efficacy of hydrophobic chemotherapeutic drugs is an intrinsic limitation to successful chemotherapy. In the present study, a multi-task delivery system based on arginine-glycine-aspartic acid peptide (RGD) decorated vitamin E succinate (VES)-grafted-chitosan oligosaccharide (CSO)/RGD-conjugated D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS-RGD) mixed micelles (VeC/T-RGD MM) was first prepared for targeted delivery of paclitaxel (PTX), a hydrophobic anticancer drug, to improve the efficacy of U87MG tumor therapy...
February 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28211700/from-genotype-to-phenotype-cytochrome-p450-2d6-mediated-drug-clearance-in-humans
#11
Jie Gao, Xin Tian, Jun Zhou, Ming-Zhu Cui, Hai-Feng Zhang, Na Gao, Qiang Wen, Hai-Ling Qiao
How genotypic variation results in phenotypic differences is still a challenge for biology. In the field of drug metabolism the means by which specific cytochrome P4502D6 (CYP2D6) genotypes yield different phenotypes at various levels (molecular, cellular, and organismal) is an important question, as differences in CYP2D6 activity can contribute to adverse drug reactions. Herein, the genotype of CYP2D6 was determined along with the absolute content of CYP2D6 and microsomal protein per gram of liver in human liver microsomes, the molecular, cellular (microsomal, tissue, organ), and organismal phenotype of CYP2D6 determined; the effect of genotype on each phenotype of CYP2D6-mediated dextromethorphan clearance (CL) was delineated, and the overall genotype-phenotype relationship for CYP2D6 was charted...
February 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28165252/cocktail-of-superoxide-dismutase-and-fasudil-encapsulated-in-targeted-liposomes-slows-pah-progression-at-a-reduced-dosing-frequency
#12
Nilesh Gupta, Jahidur Rashid, Eva Nozik-Grayck, Ivan F McMurtry, Kurt R Stenmark, Fakhrul Ahsan
Currently, two or more pulmonary vasodilators are used to treat pulmonary arterial hypertension (PAH), but conventional vasodilators alone cannot reverse disease progression. In this study, we tested the hypothesis that a combination therapy comprising a vasodilator plus a therapeutic agent that slows pulmonary arterial remodeling and right heart hypertrophy is an efficacious alternative to current vasodilator-based PAH therapy. Thus, we encapsulated a cocktail of superoxide dismutase (SOD), a superoxide scavenger, and fasudil, a specific rho-kinase inhibitor, into a liposomal formulation equipped with a homing peptide, CAR...
February 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28207272/controlling-the-release-of-indomethacin-from-glass-solutions-layered-with-a-rate-controlling-membrane-using-fluid-bed-processing-part-2-the-influence-of-formulation-parameters-on-drug-release
#13
Aswin Dereymaker, Jirka Pelgrims, Frederick Engelen, Peter Adriaensens, Guy Van den Mooter
This study aimed to investigate the pharmaceutical performance of an indomethacin-polyvinylpyrrolidone (PVP) glass solution applied using fluid bed processing as a layer on inert sucrose spheres, and subsequently top-coated with a release rate controlling membrane consisting of either ethyl cellulose or Eudragit RL. The implications of the addition of a pore former (PVP) and the coating medium (ethanol or water) on the diffusion and release behavior were also considered. In addition, the role of a charge interaction between drug and controlled release polymer on the release was investigated...
February 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28207270/intracellular-delivery-colloidally-stable-core-crosslinked-triblock-copolymer-micelles-with-glutathione-responsive-enhanced-drug-release-for-cancer-therapy
#14
Jung Kwon Oh, Depannita Biswas, So Young An, Yijing Li, Xiangtao Wang
Design and development of amphiphilic block copolymer-based nanocarriers exhibiting enhanced colloidal stability upon dilution in the blood and cellular glutathione-responsive rapid drug release is highly desired for tumor-targeting chemotherapy. Herein, we report a novel ABA-type triblock copolymer consisting of a hydrophilic central poly(ethylene glycol) block and two terminal hydrophobic blocks of a polymethacrylate having pendant disulfides (PHMssEt), thus PHMssEt-b-PEG-b-PHMssEt (ssTP). Aqueous self-assembly and following disulfide-exchange reaction of the resulting ssTP allows for formation of core-crosslinked micelles (CCMs) through the formation of new disulfide linkages, retaining enhanced colloidal stability in physiological condition and in the presence of proteins...
February 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28207269/a-biocompatible-injectable-hydrogel-with-potent-wound-healing-and-antibacterial-properties
#15
Jiaul Hoque, Relekar G Prakash, Krishnamoorthy Paramanandham, Bibek R Shome, Jayanta Haldar
Two component injectable hydrogels that cross-link in-situ have been used as non-invasive wound-filling devices, i.e., sealants. These materials carry a variety of functions at the wound sites such as seal leaks, cease unwanted bleeding, bind tissues together, and assist in wound healing process. However, commonly used sealants typically lack antibacterial properties. Since bacterial infection at the wound site is very common, bioadhesive materials with intrinsic antibacterial properties are urgently required...
February 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28206770/controlling-the-release-of-indomethacin-from-glass-solutions-layered-with-a-rate-controlling-membrane-using-fluid-bed-processing-part-1-surface-and-cross-sectional-chemical-analysis
#16
Aswin Dereymaker, David J Scurr, Elisabeth D Steer, Clive J Roberts, Guy Van den Mooter
Fluid bed coating has been shown to be a suitable manufacturing technique to formulate poorly soluble drugs in glass solutions. Layering inert carriers with a drug-polymer mixture enables these beads to be immediately filled into capsules, thus avoiding additional, potentially destabilizing, downstream processing. In this study fluid bed coating is proposed for the production of controlled release dosage forms of glass solutions by applying a second, rate controlling membrane on top of the glass solution. Adding a second coating layer adds to the physical and chemical complexity of the drug delivery system so a thorough understanding of the physical structure and phase behavior of the different coating layers is needed...
February 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28206769/extensive-chemical-modifications-in-the-primary-protein-structure-of-igg1-subvisible-particles-are-necessary-for-breaking-immune-tolerance
#17
Bjoern Boll, Juliana Bessa, Emilien Folzer, Anacelia Ríos Quiroz, Roland Schmidt, Patrick Bulau, Christof Finkler, Hanns-Christian Mahler, Jörg Huwyler, Antonio Iglesias, Atanas V Koulov
A current concern with the use of therapeutic proteins is the likely presence of aggregates and submicron, subvisible and visible particles. It has been proposed that aggregates and particles may lead to unwanted increases in immune response with a possible impact on safety or efficacy. The aim of this study was thus to evaluate the ability of subvisible particles of a therapeutic antibody to break immune tolerance in an IgG1 transgenic mouse model and to understand the particle attributes that may play a role in this process...
February 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28118715/hybrid-alginate-protein-coated-graphene-oxide-microcapsules-enhance-the-functionality-of-erythropoietin-secreting-c2c12-myoblasts
#18
Laura Saenz Del Burgo, Jesús Ciriza, Argia Acarregui, Haritz Gurruchaga, Francisco Javier Blanco, Gorka Orive, Rosa María Hernández, Jose Luis Pedraz
The beneficial effect of combining alginate hydrogel with graphene oxide (GO) on microencapsulated C2C12-myoblast viability has recently been described. However, the commercially available GO lacks homogeneity in size, this parameter being of high relevance for the cell fate in two-dimensional studies. In three-dimensional applications the capacity of this material for binding different kinds of proteins can result in the reduction of de novo released protein that can effectively reach the vicinity of the microcapsules...
February 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28199791/unpredictable-performance-of-ph-dependent-coatings-accentuates-the-need-for-improved-predictive-in-vitro-test-systems
#19
Jozef Al-Gousous, Yasuhiro Tsume, Maoqi Fu, Isam Salem, Peter Langguth
First introduced in the second half of the nineteenth century, enteric coatings are commonly used to protect acid-labile drugs, reduce the risk of gastric side effects due to irritating drugs or for local drug delivery to the lower gastrointestinal (GI) tract. The currently available enteric-coatings are based on pH-sensitive weakly acidic polymers. Despite the long history of their use, the causes behind their performance often being unpredictable have not been properly investigated with most of the attention being focused only on the gastric emptying...
February 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28199112/mitochondrial-gene-therapy-advances-in-mitochondrial-gene-cloning-plasmid-production-and-nanosystems-targeted-to-mitochondria
#20
Eduarda Coutinho, Cátia Batista, Fani Sousa, João Queiroz, Diana Costa
Mitochondrial gene therapy seems to be a valuable and promising strategy to treat mitochondrial disorders. The use of a therapeutic vector based on mitochondrial DNA, along with its affinity to the site of mitochondria can be considered a powerful tool in the reestablishment of normal mitochondrial function. In line with this and for the first time, we successfully cloned the mitochondrial gene ND1 that was stably maintained in multi-copy pCAG-GFP plasmid, used to transform E. coli. This mitochondrial gene based plasmid was encapsulated into nanoparticles...
February 15, 2017: Molecular Pharmaceutics
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