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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/29154550/biophysical-and-sequence-based-methods-for-identifying-monovalent-and-bivalent-antibodies-with-high-colloidal-stability
#1
Magfur E Alam, Steven B Geng, Christian Bender, Seth D Ludwig, Lars Linden, Rene Hoet, Peter M Tessier
In vitro antibody discovery and/or affinity maturation are often performed using antibody fragments (Fabs), but most monovalent Fabs are reformatted as bivalent IgGs (monoclonal antibodies, mAbs) for therapeutic applications. One problem related to reformatting antibodies is that the bivalency of mAbs can lead to increased antibody self-association and poor biophysical properties (e.g., reduced antibody solubility and increased viscosity). Therefore, it is important to identify monovalent Fabs early in the discovery and/or optimization process that will display favorable biophysical properties when reformatted as bivalent mAbs...
November 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29148802/ppb-peptide-mediated-sirna-loaded-stable-nucleic-acid-lipid-nanoparticles-on-targeting-therapy-of-hepatic-fibrosis
#2
Zongxiang Jia, Yan Gong, Yufang Pi, Xueying Liu, Lipeng Gao, Liqing Kang, Jing Wang, Fan Yang, Jie Tang, Weiyue Lu, Qinghua Li, Wei Zhang, Zhiqiang Yan, Lei Yu
Hepatic fibrosis is a necessary process in the development of liver diseases such as hepatic cirrhosis and its complications, which has become a serious threat to human health. Currently, antifibrotic drug treatment is ineffective, and one of the reasons should be the lack of liver targeting ability. In this report, polypeptide pPB modified stable nucleic acid lipid nanoparticles (pPB-SNALP) were prepared to selectively deliver siRNAs against heat shock protein 47 (HSP47) to liver for targeted therapy of hepatic fibrosis...
November 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29121767/from-pulmonary-surfactant-synthetic-kl4-peptide-as-effective-sirna-delivery-vector-for-pulmonary-delivery
#3
Yingshan Qiu, Michael Y T Chow, Wanling Liang, Winnie W Y Chung, Judith C W Mak, Jenny K W Lam
Pulmonary delivery of small interfering RNA (siRNA) has huge potential for the treatment of a wide range of respiratory diseases. The ability of naked siRNA to transfect cells in the lungs without a delivery vector has prompted the investigation of whether an endogenous component is at least partially responsible for the cellular uptake of siRNA, and whether a safe and efficient delivery system could be developed from this component to further improve the transfection efficiency. Surfactant protein B (SP-B), a positively charged protein molecule found in lung surfactant, is one of the possible candidates...
November 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29099601/interactions-between-chloramphenicol-carrier-polymers-and-bacteria-implications-for-designing-electrospun-drug-delivery-systems-countering-wound-infection
#4
Liis Preem, Mohammad Mahmoudzadeh, Marta Putrinš, Andres Meos, Ivo Laidmäe, Tavo Romann, Jaan Aruväli, Riinu Härmas, Artturi Koivuniemi, Alex Bunker, Tanel Tenson, Karin Kogermann
Antibacterial drug-loaded electrospun nano- and microfibrous dressings are of major interest as novel topical drug delivery systems in wound care. In this study, chloramphenicol (CAM)-loaded polycaprolactone (PCL) and PCL/poly(ethylene oxide) (PEO) fiber mats were electrospun and characterized in terms of morphology, drug distribution, physicochemical properties, drug release, swelling, cytotoxicity, and antibacterial activity. Computational modeling together with physicochemical analysis helped to elucidate possible interactions between the drug and carrier polymers...
November 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29091447/probing-pharmaceutical-mixtures-during-milling-the-potency-of-low-frequency-raman-spectroscopy-in-identifying-disorder
#5
Greg Walker, Philipp Römann, Bettina Poller, Korbinian Löbmann, Holger Grohganz, Jeremy S Rooney, Gregory S Huff, Geoffrey P S Smith, Thomas Rades, Keith C Gordon, Clare J Strachan, Sara J Fraser-Miller
This study uses a multimodal analytical approach to evaluate the rates of (co)amorphization of milled drug and excipient and the effectiveness of different analytical methods in detecting these changes. Indomethacin and tryptophan were the model substances, and the analytical methods included low-frequency Raman spectroscopy (785 nm excitation and capable of measuring both low- (10 to 250 cm(-1)) and midfrequency (450 to 1800 cm(-1)) regimes, and a 830 nm system (5 to 250 cm(-1))), conventional (200-3000 cm(-1)) Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffraction (XRPD)...
November 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29141152/tm-values-and-unfolded-fraction-can-predict-aggregation-rates-for-gcsf-variant-formulations-but-not-under-predominantly-native-conditions
#6
Mathew J Robinson, Paul Matejtschuk, Adrian F Bristow, Paul A Dalby
Protein engineering and formulation optimisation strategies can be taken to minimise protein aggregation in the biopharmaceutical industry. Short-term stability measures such as the mid-point transition temperature (Tm) for global unfolding provide convenient surrogates for longer-term (eg 2-year) degradation kinetics, with which to optimise formulations on practical time-scales. While successful in some cases, their limitations have not been fully evaluated or understood. Tm values are known to correlate with chemical degradation kinetics for wild-type granulocyte colony stimulating factor (GCSF) at pH 4-5...
November 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29141139/the-effect-of-synthetic-high-density-lipoproteins-modification-with-polyethylene-glycol-on-pharmacokinetics-and-pharmacodynamics
#7
Dan Li, Maria V Fawaz, Emily E Morin, Ran Ming, Denis Sviridov, Jie Tang, Rose Ackerman, Karl Olsen, Alan T Remaley, Anna Schwendeman
Synthetic high density lipoprotein nanoparticles (sHDL) capable of mobilizing excess cholesterol from atherosclerotic arteries and delivering it to the liver for elimination have been shown to reduce plaque burden in patients. Unfortunately, sHDLs have a narrow therapeutic index and relative to the endogenous HDL shorter circulation half-life. Surface modification with polyethylene glycol (PEG) was investigated for its potential to extend sHDL circulation in vivo. Various amounts (2.5, 5 and 10%) and different chain lengths (2 and 5 kDa) of PEG-modified lipids were incorporated in sHDL's lipid membrane...
November 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29140712/high-expression-of-ugt1a1-1a6-in-monkey-small-intestine-comparison-of-protein-expression-levels-of-cytochromes-p450-udp-glucuronosyltransferases-and-transporters-in-small-intestine-of-cynomolgus-monkey-and-human
#8
Takanori Akazawa, Yasuo Uchida, Eisuke Miyauchi, Masanori Tachikawa, Sumio Ohtsuki, Tetsuya Terasaki
Cynomolgus monkeys have been widely used for the prediction of drug absorption in humans. The purpose of this study was to clarify the regional protein expression levels of cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UGTs), and transporters in small intestine of cynomolgus monkey using liquid chromatography-tandem mass spectrometry, and to compare them with the corresponding levels in human. UGT1A1 in jejunum and ileum were >4.57- and >3.11-fold, and UGT1A6 in jejunum and ileum were >16...
November 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29140707/grapefruit-flavonoid-naringenin-regulates-the-expression-of-lxr%C3%AE-in-thp-1-macrophages-by-modulating-amp-activated-protein-kinase
#9
Javier Saenz, Consuelo Santa-María, Maria Edith Reyes-Quiroz, Isabel Geniz, Juan Jiménez, Francisco Sobrino, Gonzalo Alba
The present work investigates the modulation of grapefruit flavonoid naringenin over Liver X Receptor alpha (LXRα) and its target genes in THP-1 macrophages, focusing on AMP-activated protein kinase (AMPK) implication. Naringenin induced LXRα at mRNA and protein levels besides influencing the expression of LXRα target genes ABCA1, ABCG1 (ATP-binding cassette A1 and G1), and SREBP1c (sterol response element binding protein 1c) in THP-1 macrophages. The increased LXRα mRNA and protein expression was reverted when AMPK was inhibited by its chemical inhibitor, compound C or by transfection with AMPK α1 and α2 siRNA...
November 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29140706/a-galactosylated-pro-drug-of-ursodeoxycholic-acid-design-synthesis-characterization-and-pharmacological-effects-in-a-rat-model-of-estrogen-induced-cholestasis
#10
Francesca Di Guida, Claudio Pirozzi, Salvatore Magliocca, Anna Santoro, Adriano Lama, Roberto Russo, Maria Nieddu, Lucia Burrai, Gianpiero Boatto, Maria Pina Mollica, Federica Sodano, Loretta Lazzarato, Konstantin Chegaev, Rosaria Meli, Giuseppina Mattace Raso, Maria Grazia Rimoli
Ursodeoxycholic acid (UDCA) is considered the first-choice therapy for cholestatic disorders. To enhance solubility and exploit specific transporters in liver, we synthesized a new galactosyl pro-drug of UDCA (UDCAgal). Ethinylestradiol (EE)-induced cholestasis was used to study and compare the effects of UDCAgal with UDCA on bile flow, hepatic canalicular efflux transporter expression, and inflammation. UDCAgal resulted quite stable both at pH 7.4 and 1.2 and regenerated the parent drug after incubation in human plasma...
November 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29135265/evaluation-of-early-therapeutic-effects-after-near-infrared-photoimmunotherapy-nir-pit-using-luciferase-luciferin-photon-counting-and-fluorescence-imaging
#11
Yasuhiro Maruoka, Tadanobu Nagaya, Yuko Nakamura, Kazuhide Sato, Fusa Ogata, Shuhei Okuyama, Peter L Choyke, Hisataka Kobayashi
Near infrared photoimmunotherapy (NIR-PIT) is a newly-developed cancer treatment that induces highly selective immunogenic cell death. It is based on an antibody-photo-absorber conjugate (APC) that is activated by NIR light. The purpose of this study was to investigate the effects of NIR-PIT as measured by luciferase-luciferin photon-counting and fluorescence imaging. Six days after subcutaneous injection of A431-luc-GFP cells tumors formed in a xenograft mouse model. The EGFR-targeting antibody, panitumumab was conjugated to the photoabsorber, IRDye-700DX (pan-IR700) and was intravenously administered to tumor-bearing mice...
November 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29096443/characteristics-of-artemether-loaded-poly-lactic-co-glycolic-acid-microparticles-fabricated-by-coaxial-electrospray-validation-of-enhanced-encapsulation-efficiency-and-bioavailability
#12
Farhana Akbar Mangrio, Pankaj Dwivedi, Shuya Han, Gang Zhao, Dayong Gao, Ting Si, Ronald X Xu
Artemether is one of the most effective drugs for the treatment of chloroquine-resistant and Plasmodium falciparum strains of malaria. However, its therapeutic potency is hindered by its poor bioavailability. To overcome this limitation, we have encapsulated artemether in poly(lactic-co-glycolic) acid (PLGA) core-shell microparticles (MPs) using the coaxial electrospray method. With optimized process parameters including liquid flow rates and applied electric voltages, experiments are systematically carried out to generate a stable cone-jet mode to produce artemether-loaded PLGA-MPs with an average size of 2 μm, an encapsulation efficiency of 78 ± 5...
November 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29130688/from-classification-to-regression-multitasking-qsar-modeling-using-a-novel-modular-neural-network-simultaneous-prediction-of-anticonvulsant-activity-and-neurotoxicity-of-succinimides
#13
Davor Antanasijević, Jelena Antanasijević, Nemanja Trišović, Gordana Ušćumlić, Viktor Pocajt
Succinimides, which contain a pharmacophore responsible for anticonvulsant activity, are frequently used antiepileptic drugs and the synthesis of their new derivatives with improved efficacy and tolerability presents an important task. Nowadays, multitarget/tasking methodologies focused on quantitative-structure activity relationships (mt-QSAR/mtk-QSAR) have an important role in the rational design of drugs since they enable simultaneous prediction of several standard measures of biological activities at diverse experimental conditions and against different biological targets...
November 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29111753/biogenic-nanostructured-porous-silicon-as-a-carrier-for-stabilization-and-delivery-of-natural-therapeutic-species
#14
Nguyen T Le, Jhansi R Kalluri, Armando Loni, Leigh T Canham, Jeffery L Coffer
Nanostructured mesoporous silicon (pSi) derived from the silicon-accumulator plant Tabasheer (Bambuseae) is demonstrated to serve as a potential carrier matrix for carrying and stabilizing naturally active, but otherwise metastable, therapeutic agents. Particularly, in this study, garlic oil containing phytochemicals (namely, allicin) that are capable of inhibiting Staphylococcus aureus (S. aureus) bacterial growth were incorporated into Tabasheer-derived porous silicon. Thermogravimetric analysis (TGA) indicated that relatively high amounts of the extract (53...
November 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29091448/insights-on-the-mechanism-of-action-of-inh-c10-as-an-antitubercular-prodrug
#15
Diogo Vila-Viçosa, Bruno L Victor, Jorge Ramos, Diana Machado, Miguel Viveiros, Jacek Switala, Peter C Loewen, Ruben Leitão, Filomena Martins, Miguel Machuqueiro
Tuberculosis remains one of the top causes of death worldwide, and combating its spread has been severely complicated by the emergence of drug-resistance mutations, highlighting the need for more effective drugs. Despite the resistance to isoniazid (INH) arising from mutations in the katG gene encoding the catalase-peroxidase KatG, most notably the S315T mutation, this compound is still one of the most powerful first-line antitubercular drugs, suggesting further pursuit of the development of tailored INH derivatives...
November 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29129076/comprehensive-molecular-characterization-of-a-cisplatin-specific-monoclonal-antibody
#16
Lena Ruhe, Stefanie Ickert, Ulrike Hochkirch, Johanna Hofmann, Sebastian Beck, Jürgen Thomale, Michael W Linscheid
Despite their immense and rapidly increasing importance as analytical tools or therapeutic drugs, the detailed structural features of particular monoclonal antibodies are widely unknown. Here, an antibody already in use for diagnostic purposes and for molecular dosimetry studies in cancer therapy with very high affinity and specificity for cisplatin-induced DNA modifications was studied extensively. The molecular structure and modifications as well as the antigen specificity were investigated mainly by mass spectrometry...
November 11, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29125768/self-assembling-elastin-like-hydrogels-for-timolol-delivery-development-of-an-ophthalmic-formulation-against-glaucoma
#17
Alicia Fernández-Colino, Daniela A Quinteros, Daniel A Allemandi, Alessandra Girotti, Santiago D Palma, F Javier Arias
This work focuses on improving the effectiveness of current therapies against glaucoma by incorporating self-assembled polymers into the ophthalmic formulation. To that end, we first studied the influence of the dispersing medium on the mechanical performance of self-assembling elastin-like (EL) and silk-elastin like (SEL) hydrogels by conducting rheological tests. These polymers were subsequently incorporated into the anti-glaucoma formulation, which contains timolol maleate (TM) as active ingredient, and in vivo tests, namely adhesion tests and intraocular pressure measurements (IOP), were performed in New Zealand rabbits...
November 10, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29125764/selective-acceleration-of-crystal-growth-of-indomethacin-polymorphs-by-low-concentration-poly-ethylene-oxide
#18
Qin Shi, Jie Zhang, Chen Zhang, Jing Jiang, Jun Tao, Dongshan Zhou, Ting Cai
Physical stability of pharmaceutical amorphous solid dispersions is one of the critical attributes to the successful development of the formulation. Herein, we studied the impact of low-concentration poly(ethylene oxide) (PEO) on the crystallization rates of three polymorphs of indomethacin (IMC, γ, α and δ-form). We observed that the addition of 3% w/w PEO significantly increased the crystal growth rates of γ-form and α-from of IMC, but had a negligible effect on the δ-form. The reduction of the activation energy for the crystal growth of IMC polymorphs after adding the PEO follows the order γ-form > α-form > δ-form, which is consistent with the trend toward the accelerating effects of PEO on the crystal growth rates of three polymorphs...
November 10, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29091446/insight-into-flufenamic-acid-cocrystal-dissolution-in-the-presence-of-a-polymer-in-solution-from-single-crystal-to-powder-dissolution
#19
Minshan Guo, Ke Wang, Ning Qiao, László Fábián, Ghazala Sadiq, Mingzhong Li
Effects of three polymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and copolymer of vinylpyrrolidone/vinyl acetate (PVP-VA), on the dissolution behavior of the cocrystals of flufenamic acid with theophylline (FFA-TP CO) and nicotinamide (FFA-NIC CO) were investigated at multiple length scales. At the molecular level, the interactions of crystal surfaces with a polymer were analyzed by observing etching pattern changes using atomic force microscopy. At the macroscopic scale, dissolution rates of particular faces of a single crystal were determined by measurement of the physical retreat velocities of the faces using optical light microscopy...
November 10, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29120644/acid-induced-intracellular-dissociation-of-%C3%AE-cyclodextrin-threaded-polyrotaxanes-directed-toward-attenuating-phototoxicity-of-bisretinoids-through-promoting-excretion
#20
Atsushi Tamura, Moe Ohashi, Kei Nishida, Nobuhiko Yui
In the retinal pigment epithelium of patients with age-related macular degeneration (AMD), excess N-retinylidene-N-retinylethanolamine (A2E), a dimer of all-trans-retinal, accumulats to induce inflammatory cytokine secretion and phototoxic effects. Therefore, the reduction of intracellular A2E is a promising approach for the prevention and treatment of AMD. In this study, acid-labile β-cyclodextrin (β-CD)-threaded polyrotaxanes (PRXs) were synthesized and investigated their effects on the removal of A2E accumulated in retinal pigment epithelium cells (ARPE-19) in comparison to nonlabile PRXs and 2-hydroxypropyl β-CD (HP-β-CD) were examined...
November 9, 2017: Molecular Pharmaceutics
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