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Molecular Pharmaceutics

Jianquan Yang, Jingli Xu, Lina Cheuy, Rene Gonzalez, Darrell R Fisher, Yubin Miao
The purpose of this study is to examine the melanocortin-1 receptor (MC1R) targeting and specificity of 203Pb-DOTA-GGNle-CycMSHhex in melanoma cells and tumors to facilitate its potential therapeutic application when labeled with 212Pb. The melanocortin-1 receptor (MC1R)-specific targeting and imaging properties of 203Pb-DOTA-GGNle-CycMSHhex were determined on B16/F1 and B16/F10 murine melanoma cells, and in B16/F1 flank melanoma-, B16/F10 flank melanoma- and B16/F10 pulmonary metastatic melanoma-bearing C57 mice...
February 14, 2019: Molecular Pharmaceutics
Lihong Cheng, Makoto Muroi, Shining Cao, Linglin Bian, Hiroyuki Osada, Lan Xiang, Jianhua Qi
3β,23,28-Trihydroxy-12-oleanene 3β-caffeate (compound 1) is a neuritogenic pentacyclic triterpenoid, which was isolated from Desmodium sambuense based on a PC12 cell bioassay system. Compound 1 induced neurite outgrowth dose-dependently in PC12 cells and primary cortical neurons at doses of 0.1, 0.3 and 1 μM. The potential target of compound 1 was predicted by ChemProteoBase profiling, and the mechanism of action was investigated using specific inhibitors, western blot analysis, and PC12 (rasN17) and PC12 (mtGAP) mutants...
February 14, 2019: Molecular Pharmaceutics
Theerthankar Das, Huai-Jin Choong, Yee Chin Kwang, Hak-Kim Chan, Jim Manos, Philip Chi Lip Kwok, Hien T T Duong
Antibiotic resistance in pathogenic bacteria has emerged as a big challenge to human and animal health and significant economy loss worldwide. Development of novel strategies to tackle antibiotic resistance is of the utmost priority. In this study, we combined glutathione (GSH), a master antioxidant in all mammalian cells, and nitric oxide, a proven biofilm-dispersing agent, to produce GSNO. Resazurin biofilm viability assay, crystal violet biofilm assay, and confocal microscopy techniques showed that GSNO disrupted biofilms of both P...
February 14, 2019: Molecular Pharmaceutics
Xu Zhou, Xi Cao, He Tu, Zhi-Rong Zhang, Li Deng
Celastrol (CLT)-loaded PEG-PLGA nanoparticles (NPs/CLT) coated with neutrophil membranes (NNPs/CLT) were explored for the management of acute pancreatitis. PEG-PLGA nanoparticles sized around 150 nm were proven to selectively accumulate in the pancreas in rats with acute pancreatitis (AP). NNPs were found to overcome the blood-pancreas barrier and specifically distributed to the pancreatic tissues. Moreover, NNPs showed more selective accumulation in the pancreas than nanoparticles without any membrane coating in AP rats...
February 12, 2019: Molecular Pharmaceutics
Lei Jiang, Hong Zhu, Yi Li, Xiaodong Wu, Huoqiang Wang, Zhen Cheng
Integrin αvβ3 has been considered as a promising biomarker for vulnerable atherosclerotic plaques, and it is highly expressed by those instability associated factors such as macrophages, vessel endothelial cells and smooth muscle cells. Our previous study successfully showed that 64Cu-labeled divalent (containing two RGD motifs) cystine knot peptide, 64Cu-NOTA-3-4A, had high binding affinity and specificity in targeting vulnerable carotid atherosclerotic plaques with increased αvβ3 levels. Therefore, considering that 68Ga has excellent nuclear physical properties for positron emission tomography (PET), this study aimed to investigate the feasibility of using 68Ga-NOTA-3-4A for PET study of vulnerable atherosclerotic plaques...
February 11, 2019: Molecular Pharmaceutics
Zubida M Al-Majdoub, Hajar Al Feteisi, Brahim Achour, Stacey Warwood, Sibylle Neuhoff, Amin Rostami-Hodjegan, Jill Barber
The blood-brain barrier (BBB) maintains brain homeostasis by controlling traffic of molecules from the circulation into the brain. This function is predominantly dependent on proteins expressed at the BBB, especially transporters and tight junction proteins. Alterations to the level and function of BBB proteins can impact the susceptibility of the central nervous system to exposure to xenobiotics in the systemic circulation with potential consequent effects on brain function. In this study, expression profiles of drug transporters and solute carriers in the BBB were assessed in tissues from healthy individuals ( n = 12), Alzheimer's patients ( n = 5), and dementia with Lewy bodies patients ( n = 5), using targeted, accurate mass retention time (AMRT) and global proteomic methods...
February 8, 2019: Molecular Pharmaceutics
Xabier Rios, Marta Compte, Vanessa Gómez-Vallejo, Unai Cossío, Zuriñe Baz, Miguel Angel Morcillo, Pedro Ramos-Cabrer, Luis Alvarez-Vallina, Jordi Llop
Monoclonal antibodies (mAbs) are currently used as therapeutic agents in different types of cancer. However, mAbs and antibody fragments developed so far show suboptimal properties in terms of circulation time and tumor penetration/retention. Here, we report the radiolabeling, pharmacokinetic evaluation, and determination of tumor targeting capacity of the previously validated anti-CEA MFE23-scFv-based N-terminal trimerbody (MFE23N-trimerbody), and the results are compared to those obtained for the monomeric MFE23-scFv...
February 6, 2019: Molecular Pharmaceutics
Songye Li, MingQiang Zheng, Mika Naganawa, Hong Gao, Richard Pracitto, Anupama Shirali, Shu-Fei Lin, Jo-Ku Teng, Jim Ropchan, Yiyun Huang
The kappa opioid receptor (KOR) is involved in depression, alcoholism and drug abuse. The current agonist radiotracer 11 C-GR103545 is not ideal for imaging KOR due to its slow tissue kinetics in human. The aim of our project was to develop novel KOR agonist radiotracers with improved imaging properties. A novel compound FEKAP (( R)-4-(2-(3,4-dichlorophenyl)acetyl)-3-((ethyl(2-fluoroethyl)amino)methyl) piperazine-1-carboxylate) was designed, synthesized and assayed for in vitro binding affinities. It was then radiolabeled and evaluated in rhesus monkeys...
February 6, 2019: Molecular Pharmaceutics
Huilong Luo, Elisa Rossi, Bruno Saubamea, Stéphanie Chasseigneaux, Véronique Cochois, Nina Choublier, Maria Smirnova, Fabienne Glacial, Nicolas Perrière, Sandrine Bourdoulous, David M Smadja, Marie-Claude Menet, Pierre-Olivier Couraud, Salvatore Cisternino, Xavier Declèves
The effect of cannabidiol (CBD), a high-affinity agonist of the transient receptor potential vanilloid-2 (TRPV2) channel, has been poorly investigated in human brain microvessel endothelial cells (BMEC) forming the blood-brain barrier (BBB). TRPV2 expression and its role on Ca2+ cellular dynamics, trans-endothelial electrical resistance (TEER), cell viability and growth, migration, and tubulogenesis were evaluated in human primary cultures of BMEC (hPBMEC) or in the human cerebral microvessel endothelial hCMEC/D3 cell line...
February 5, 2019: Molecular Pharmaceutics
Yuan Chen, Elizabeth M Topp
Interactions of a lyophilized peptide with water and excipients in the solid matrix were explored using photolytic labeling. A model peptide "KLQ" (Ac-QELHKLQ-NHCH3) was covalently labeled with NHS-diazirine (succinimidyl 4,4'-azipentanoate) and the labeled peptide (KLQ-SDA) was formulated and exposed to UV light in both solution and lyophilized solids. Solid samples contained the following excipients at a molar ratio of 1:400: sucrose, trehalose, mannitol, histidine or arginine. Prior to UV exposure, the lyophilized solids were exposed to various relative humidity (RH) environments (8%, 13%, 33%, 45% and 78%) and the resulting solid moisture content (Karl Fischer titration) and glass transition temperature (Tg; differential scanning calorimetry, DSC) were measured...
February 5, 2019: Molecular Pharmaceutics
Raghvendra Pratap Singh, Tania Hidalgo, Pierre-Andre Cazade, Raphael Darcy, Michael Cronin, Irina Dorin, Caitriona M O'Driscoll, Damien Thompson
Functionalised cyclodextrin molecules assemble into a wide variety of superstructures in solution, which are of interest for drug delivery and other nanomaterial and biomaterial applications. Here we use a combined simulation and experimental approach to probe the co-assembly of siRNA and cationic cyclodextrin (c-CD) derivatives into a highly stable gene delivery nanostructure. The c-CD form supramolecular structures via interdigitation of their aliphatic tails, analogous to the formation of lipid bilayers and micelles...
February 5, 2019: Molecular Pharmaceutics
Jie Zhang, Qin Shi, Jun Tao, Yayun Peng, Ting Cai
Amorphous solid dispersions have been widely used as an effective formulation strategy in the oral delivery of poorly soluble drugs. However, one of the main challenges in the development of amorphous drugs is to maintain their physical stability. The underlying mechanism of amorphous drugs crystallized in polymeric matrices is still poorly understood. In this study, we report the phenomenon of polymer enrichment at the crystal-liquid interface during the crystallization of griseofulvin (GSF) in the presence of poly (ethylene oxide) (PEO)...
February 4, 2019: Molecular Pharmaceutics
Masami Ukawa, Sohei Tanishita, Haruya Yagi, Yuki Yoshida, Takumi Tomono, Koichi Shigeno, Etsuo Tobita, Tomofumi Uto, Masanori Baba, Shinji Sakuma
We have been investigating the potential use of polymers modified with cell-penetrating peptides as an adjuvant for mucosal vaccination and have already developed nondegradable poly( N-vinylacetamide- co-acrylic acid) (PNVA- co-AA) with which d-octaarginine, a typical cell-penetrating peptide, was grafted. Our previous murine infection experiments demonstrated that immunoglobulin G (IgG) and immunoglobulin A (IgA) were induced in systemic circulation and secreted on nasal mucosa, respectively, through 4-time nasal inoculations with a mixture of influenza viral antigens and d-octaarginine-linked PNVA- co-AA at 7-day intervals, and that immunized mice were perfectly protected from homologous virus infection...
February 4, 2019: Molecular Pharmaceutics
Shin Hye Ahn, Daniel Thach, Brett A Vaughn, Vincent M Alford, Alyssa N Preston, Scott T Laughlin, Eszter Boros
We report the nuclear and optical in vitro and in vivo imaging of SKOV-3 cells by targeting HER2 with a bimodal trastuzumab conjugate. Previously, we have shown that desferrichrome derivatives provide a robust and versatile radiolabeling platform for the radioisotope zirconium-89. Here, we appended silicon-rhodamine functionalized linear desferrichrome to trastuzumab. This construct was radiolabeled and used to image cellular binding and antibody uptake in vitro and in vivo. The robust extinction coefficient of the SiR deep-red emissive fluorophore enables direct quantification of the number of appended chelators and fluorophore molecules per antibody...
February 4, 2019: Molecular Pharmaceutics
Mikhail Durymanov, Christian Kroll, Anastasia Permyakova, Joshua Reineke
Robust deposition of extracellular matrix is a significant barrier for delivery of nanotherapeutics and small-molecule anti-cancer drugs to different tumors including pancreatic ductal adenocarcinoma. Here, we investigated permeation and total uptake of polystyrene nanoparticles of different diameters in 3D multicellular spheroid models of pancreatic tumors. Special attention was given to analysis of the impact of endocytic processes on nanoparticle accumulation and distribution in spheroids. We generated spheroids of BxPC3 or PANC-1 cells, able to internalize 20 nm, 100 nm and 500 nm fluorescent polystyrene beads with different efficacies, resulting in 20 nm > 100 nm > 500 nm and 100 nm > 500 nm > 20 nm trends, respectively...
February 1, 2019: Molecular Pharmaceutics
Christina Leichner, Patrizia Wulz, Randi Angela Baus, Claudia Menzel, Sina Katharina Götzfried, Ronald Gust, Andreas Bernkop-Schnürch
AIM: The objective of the study was to compare polyacrylic acid-N-hydroxysulfosuccinimide reactive esters (PAA-Sulfo-NHS) and polyacrylic acid-cysteine conjugates (PAA-Cys) regarding their mucoadhesiveness. METHODS: Polymer conjugates were synthesized in a water free environment and characterized by UV/VIS spectroscopy and FTIR. Water uptake studies were performed and the polymers were further examined for their mucoadhesive properties and cohesiveness using the rotating cylinder method...
February 1, 2019: Molecular Pharmaceutics
Alberto Busi, Annalisa Aluigi, Andrea Guerrini, Carla Boga, Giorgio Sartor, Natalia Calonghi, Giovanna Sotgiu, Tamara Posati, Franco Corticelli, Jessica Fiori, Greta Varchi, Claudia Ferroni
Histone deacetylases, HDACs, have been demonstrated to play a critical role in epigenetic signaling and were found to be overexpressed in several type of cancers, therefore they represent valuable targets for anticancer therapy. 9-Hydroxystearic acid has been shown to bind the catalytic site of HDAC1, inducing G0/G1 phase cell cycle arrest and activation of p21WAF1 gene, thus promoting cells growth inhibition and differentiation in many cancer cells. Despite the (R) enantiomer of 9-hydroxystearic acid (9R) displayed promising in vitro growth-inhibitory effect on HT29 cell line, its scarce water solubility and micromolar activity require novel solutions for improving its efficacy and bioavailability...
January 31, 2019: Molecular Pharmaceutics
Laura Weber, Xiaobei Wang, Rongguo Ren, Xin Wei, Gang Zhao, Junxiao Yang, Hongjiang Yuan, Huiling Pang, Hanjun Wang, Dong Wang
The addictive potential of clinically-used opioids due to their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction...
January 31, 2019: Molecular Pharmaceutics
Gavin P Andrews, Shu Li, Ammar Almajaan, Tao Yu, Luigi Martini, Anne Marie Healy, David S Jones
Hyperlipidaemia is considered as one of the main risk factors associated with cardiovascular diseases (CVDs). Among different lipid-lowering agents used to manage hyperlipidaemia, statins are highly prescribed for management of hyperlipidaemia with simvastatin being one of the most common. Simvastatin is susceptible to extensive metabolism by CYP450 3A4 and 3A5 which are expressed both in the liver and the gastrointestinal tract. Nevertheless, the localization of these enzymes is site dependent with lower concentration at the distal/proximal regions of the small intestine/colon...
January 31, 2019: Molecular Pharmaceutics
Sanjeev Kothari, Radha Vippagunta
The conformational flexibility of organic molecules introduces more structural options for crystallization to occur, but has potential complications, such as, reduced crystallization tendency and conformational polymorphism. Although, a variety of energetically similar conformers could be anticipated, it is extremely difficult to predict the crystal conformation for conformationally flexible molecules. The present study investigates differences in thermodynamic pa-rameters for the free base, c-FB and an amorphous dihydrochloride salt, a-Di-HCl, of a conformationally flexible drug substance, tenapanor (RDX5791)...
January 30, 2019: Molecular Pharmaceutics
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