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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/29355022/probing-the-conformation-of-an-igg1-monoclonal-antibody-in-lyophilized-solids-using-solid-state-hydrogen-deuterium-exchange-with-mass-spectrometric-analysis-sshdx-ms
#1
Ehab M Moussa, Satish K Singh, Michael Kimmel, Sandeep Nema, Elizabeth M Topp
Therapeutic proteins are often formulated as lyophilized products to improve their stability and prolong shelf life. The stability of proteins in the solid-state has been correlated with preservation of native higher order structure and/or molecular mobility in the solid matrix, with varying success. In the studies reported here, we used solid-state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX-MS) to study the conformation of an IgG1 monoclonal antibody (mAb) in lyophilized solids and related the extent of ssHDX to aggregation during storage in the solid phase...
January 22, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29345955/investigation-of-polymer-surfactant-interactions-and-their-impact-on-itraconazole-solubility-and-precipitation-kinetics-for-developing-spray-dried-amorphous-solid-dispersions
#2
Tanvi Mahesh Deshpande, Helen Shi, John Pietryka, Stephen W Hoag, Ales Medek
Methods were developed to systematically screen different polymer-surfactant combinations for the purpose of enhancing amorphous active pharmaceutical ingredient (API) solubility while maintaining its physical stability. Itraconazole (ITZ) was chosen as the model API mostly due to its low aqueous solubility. Special attention was paid to determine the effect of a reduction in the critical micelle concentration (CMC) by specific polymer/surfactant combinations on the ITZ solubility and physical stability. However, only a slight correlation was actually found...
January 18, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29342360/sustained-delivery-of-doxorubicin-via-acetalated-dextran-scaffold-prevents-glioblastoma-recurrence-after-surgical-resection
#3
Elizabeth G Graham-Gurysh, Kathryn M Moore, Andrew B Satterlee, Kevin T Sheets, Feng-Chang Lin, Eric M Bachelder, C Ryan Miller, Shawn Hingtgen, Kristy M Ainslie
The primary cause of mortality for glioblastoma (GBM) is local tumor recurrence following standard-of-care therapies, including surgical resection. With most tumors recurring near the site of surgical resection, local delivery of chemotherapy at the time of surgery is a promising strategy. Herein drug loaded polymer scaffolds with two distinct degradation profiles were fabricated to investigate the effect of local drug delivery rate on GBM recurrence following surgical resection. The novel biopolymer, acetalated dextran (Ace-DEX), was compared to commercially available polyester, poly(L-lactide) (PLA)...
January 17, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29341619/a-new-folate-grafted-chitosan-derivative-to-improve-the-delivery-of-paclitaxel-loaded-solid-lipid-nanoparticles-for-lung-tumour-therapy-by-inhalation
#4
Remi Rosiere, Matthias Van Woensel, Michel Gelbcke, Véronique Mathieu, Julien Hecq, Thomas Mathivet, Marjorie Vermeersch, Pierre G Van Antwerpen, Karim Amighi, Nathalie Wauthoz
Inhaled chemotherapy for the treatment of lung tumours requires that drug delivery systems improve selectivity for cancer cells and tumour penetration and allow sufficient lung residence. To this end, we developed solid lipid nanoparticles (SLN) with modified surface properties. We successfully synthesized a new folate-grafted copolymer of polyethylene glycol (PEG) and chitosan, F-PEG-HTCC, with a PEG-graft ratio of 7% and a molecular weight range of 211-250 kDa. F-PEG-HTCC-coated, paclitaxel-loaded SLN were prepared with an encapsulation efficiency, mean diameter and zeta potential of about 100%, 250 nm and +32 mV, respectively...
January 17, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29341617/enhancing-docetaxel-delivery-to-multidrug-resistant-cancer-cells-with-albumin-coated-nanocrystals
#5
Sheryhan F Gad, Joonyoung Park, Ji Eun Park, Gihan N Fetih, Sozan S Tous, Wooin Lee, Yoon Yeo
Intravenous delivery of poorly water-soluble anticancer drugs such as docetaxel (DTX) is challenging due to the low bioavailability and the toxicity related to solubilizing excipients. Colloidal nanoparticles are used as alternative carriers, but low drug loading capacity and circulation instability limit their clinical translation. To address these challenges, DTX nanocrystals (NCs) were prepared using Pluronic F127 as an intermediate stabilizer and albumin as a functional surface modifier, which were previously found to be effective in producing small and stable NCs...
January 17, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29338251/delivery-of-oxytocin-to-the-brain-for-the-treatment-of-autism-spectrum-disorder-by-nasal-application
#6
Akiko Tanaka, Tomoyuki Furubayashi, Mari Arai, Daisuke Inoue, Shunsuke Kimura, Akiko Kiriyama, Kosuke Kusamori, Hidemasa Katsumi, Reiko Yutani, Toshiyasu Sakane, Akira Yamamoto
Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the blood stream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29337578/physiologically-based-pharmacokinetic-modeling-in-lead-optimization-i-evaluation-and-adaptation-of-gastroplus-to-predict-bioavailability-of-medchem-series
#7
Pankaj R Daga, Michael B Bolger, Ian S Haworth, Robert Daniel Clark, Eric J Martin
When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modified properties mainly by following experience and general rules of thumb. More quantitative models that predict %F of proposed compounds from chemical structure alone have proven elusive. Global empirical %F quantitative structure-property (QSPR) models perform poorly and projects have too little data to train local %F QSPR models. Mechanistic oral absorption and physiologically-based pharmacokinetic (PBPK) models simulate the dissolution, absorption, systemic distribution, and clearance of a drug in preclinical species and humans...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29337566/cationic-polymeric-nanoparticle-delivering-ccr2-sirna-to-inflammatory-monocytes-for-tumor-microenvironment-modification-and-cancer-therapy
#8
Song Shen, Yue Zhang, Kai-Ge Chen, Ying-Li Luo, Jun Wang
Accumulating evidence has confirmed that malignant tumors have a complex microenvironment, which consists of a heterogeneous collection of tumor cells and other cell subsets (including the full gamut of immune cells). Tumor-associated macrophages (TAMs), derived from circulating Ly6Chi monocytes, constitute the most substantial fraction of tumor-infiltrating immune cells in nearly all cancer types and contribute to tumor progression, vascularization, metastasis, immunosuppression and therapeutic resistance...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29337562/physiologically-based-pharmacokinetic-modeling-in-lead-optimization-ii-rational-bioavailability-design-by-global-sensitivity-analysis-to-identify-properties-affecting-bioavailability
#9
Pankaj R Daga, Michael B Bolger, Ian Haworth, Robert Daniel Clark, Eric J Martin
When medicinal chemists need to improve oral bioavailability (%F) during lead optimization, they systematically modify compound properties mainly based on their own experience and general rules of thumb. However, at least a dozen properties can influence %F, and the difficulty of multi-parameter optimization for such complex non-linear processes grows combinatorially with the number of variables. Furthermore, strategies can be in conflict. For example, adding a polar or charged group will generally increase solubility but decrease permeability...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29328661/investigation-of-drug-excipient-interactions-in-biclotymol-amorphous-solid-dispersions
#10
Benjamin Schammé, Nicolas Couvrat, Vincent Tognetti, Laurent Delbreilh, Valérie Dupray, Eric Dargent, Gérard Coquerel
The effect of low molecular weight excipients on drug-excipient interactions, molecular mobility and propensity to recrystallization of an amorphous active pharmaceutical ingredient is investigated. Two structurally related excipients (α-Pentaacetylglucose and β-Pentaacetylglucose), five different drug:excipient ratios (1:5, 1:2, 1:1, 2:1 and 5:1, w/w) and three different solid state characterization tools (Differential Scanning Calorimetry, X-Ray Powder Diffraction and Dielectric Relaxation Spectroscopy) were selected for the present research...
January 12, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29323913/nanoparticles-with-cd44-targeting-and-ros-triggering-property-as-effective-in-vivo-antigen-delivery-system
#11
Xiaoyu Liang, Xuanling Li, Jianwei Duan, Youlu Chen, Xiaoli Wang, Liyun Pang, Deling Kong, Bing Song, Chen Li, Jing Yang
Currently, development of subunit vaccine based on recombinant antigens or peptides has gradually become an important alternative option for traditional vaccine. However, induction of potent immune response with desired efficacy remains a major challenge. The nanoparticle-based antigen delivery system has been considered a potential carrier system to improve the efficacy of subunit vaccine. In the present study, we have designed an immune-stimulatory delivery system by conjugating three-armed PLGA to PEG via the peroxalate ester bond which is sensitive to hydrogen peroxide (H2O2), a major reactive oxygen species (ROS)...
January 11, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29323501/the-pivotal-role-of-copper-in-neurodegeneration-a-new-strategy-for-the-therapy-of-neurodegenerative-disorders
#12
Roberta Giampietro, Francesco Spinelli, Marialessandra Contino, Nicola Antonio Colabufo
Copper is an essential trace element for human body since it is a cofactor of several enzymes and proteins and plays a pivotal role in several biological functions (e.g., respiration, protection from oxidative damage, iron metabolism, etc.), also including the central nervous system development and functioning (e.g. synthesis of neurotransmitters, myelination, activation of neuropeptides, etc.). Therefore, copper dysmetabolism is associated with different toxic effects, mainly represented by oxidative stress, and it has been reported in many neurodegenerative disorders, such as Wilson's disease, Menkes disease, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis...
January 11, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29320631/thermoresponsive-co-biodegradable-linear-dendritic-nanoparticles-for-sustained-release-of-nerve-growth-factor-to-promote-neurite-outgrowth
#13
Young Shin Kim, Muhammad Gulfam, Tao L Lowe
Thermo-responsive and biodegradable linear-dendritic nanoparticles containing poly(N-isopropylacrylamide), poly(L-lactic acid) and poly(L-lysine) dendron were investigated for sustained release of nerve growth factor (NGF) in response to temperature change. The nanoparticles and their degradants were not cytotoxic to neuron-like PC12 cells for at least one month. The nanoparticles were preferentially taken up by PC12 cells 6 to 13 times more at temperature above (37 °C) than below (25 °C) the lower critical solution temperature of the nanoparticles...
January 10, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29320195/microstructure-of-pharmaceutical-semicrystalline-dispersions-the-significance-of-polymer-conformation
#14
Tu Van Duong, Bart Goderis, Jan Van Humbeeck, Guy Van den Mooter
The microstructure of pharmaceutical semicrystalline solid dispersions has attracted extensive attention due to its complexity that might result in the diversity in physical stability, dissolution behavior and pharmaceutical performance of the systems. Numerous factors have been reported that dictate the microstructure of semicrystalline dispersions. Nevertheless, the importance of the complicated conformation of the polymer has never been elucidated. In this study, we investigate the microstructure of dispersions of polyethylene glycol and active pharmaceutical ingredients by small angle X-ray scattering and high performance differential scanning calorimetry...
January 10, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29314858/panitumumab-modified-with-metal-chelating-polymers-mcp-complexed-to-111in-and-177lu-an-egfr-targeted-theranostic-for-pancreatic-cancer
#15
Sadaf Aghevlian, Yijie Lu, Mitchell A Winnik, David W Hedley, Raymond M Reilly
A metal-chelating polymer (MCP) with a polyglutamide (PGlu) backbone presenting on average 13 DOTA (tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelators for complexing 111In or 177Lu and 10 polyethylene glycol (PEG) chains to minimize liver and spleen uptake was conjugated to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), panitumumab. Since panitumumab-MCP may be dual-labeled with 111In and 177Lu for SPECT, or radioimmunotherapy (RIT) exploiting the Auger electrons or β-particle emissions, respectively, we propose that panitumumab-MCP could be a useful theranostic agent EGFR-positive PnCa...
January 9, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29313693/poloxamer-407-tpgs-mixed-micelles-as-promising-carriers-for-cyclosporine-ocular-delivery
#16
Maria Aurora Grimaudo, Silvia Pescina, Cristina Padula, Patrizia Santi, Angel Concheiro, Carmen Alvarez-Lorenzo, Sara Nicoli
Cyclosporine is an immunosuppressant agent approved for the treatment of dry eye disease and used off-label for other ocular pathologies. Its formulation and ocular bioavailability is a real challenge due to the large molecular weight (1.2 kDa), high lipophilicity and low water solubility. The aim of the work was to develop an aqueous micellar formulation for an efficient cyclosporine delivery to the ocular tissues, using a water soluble derivative of vitamin E (TPGS: d-alpha tocopheryl polyethylene glycol 1000 succinate) and a poloxamer (poloxamer 407) as excipients...
January 9, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29309158/drug-excipient-interactions-effect-on-molecular-mobility-and-physical-stability-of-ketoconazole-organic-acid-coamorphous-systems
#17
Michelle H Fung, Marla DeVault, Keith T Kuwata, Raj Suryanarayanan
The use of excipients other than polymers for enhancing the physical stability of amorphous active pharmaceutical ingredients (APIs) has largely been unexplored. We investigated several organic acids (oxalic, tartaric, citric and succinic acid) for the purpose of stabilizing a weakly basic API, ketoconazole (KTZ), in the amorphous state. Coamorphous systems with each acid, in 1:1 KTZ-acid molar ratio, were prepared by spray drying. The interaction of KTZ with each acid was investigated by FT-IR, solid-state NMR and quantum chemical calculations...
January 8, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29309155/mutual-impact-of-phase-separation-crystallization-and-water-sorption-in-amorphous-solid-dispersions
#18
Christian Luebbert, Maximilian Wessner, Gabriele Sadowski
The molecular integration of poorly-water-soluble active pharmaceutical ingredients (APIs) in a suitable polymeric matrix is a possible approach to enhance the dissolution behavior and solubility of these APIs. Like all newly-developed pharmaceutical formulations, these formulations (often denoted as amorphous solid dispersions (ASDs)) need to undergo storage stability tests at defined relative humidity (RH) and temperature conditions. In a previous work (Int. J. Pharm. 532 (2017) 635-646), it was shown that thermodynamic modeling can be successfully used to predict the long-term stability of ASDs against API crystallization and moisture-induced amorphous-amorphous phase separation (MIAPS)...
January 8, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29308904/pet-imaging-of-vcam-1-expression-and-monitoring-therapy-response-in-tumor-with-a-68ga-labeled-single-chain-variable-fragment
#19
Xiao Zhang, Chunbao Liu, Fan Hu, Yingying Zhang, Jing Wang, Yongheng Gao, Yaqun Jiang, Yongxue Zhang, Xiaoli Lan
Vascular cell adhesion molecule-1 (VCAM-1) is becoming an attractive candidate for targeting in tumor detection and therapy due to its involvement in tumorigenicity and metastasis. LY2409881, an IKK2 inhibitor, can trigger apoptosis of VCAM-1 positive melanoma cells. The aim of this study was to assess the use of the 68Ga-labeled single chain variable fragment (scFv) of VCAM-1 in detecting VCAM-1-positive tumor expression and monitoring the therapeutic effect of LY2409881. Melanoma cell lines, B16F10 and A375m, were sued as VCAM-1 overexpression and underexpression models, respectively...
January 8, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29308900/a-18f-labeled-alanine-derivative-serve-as-an-asct2-marker-for-cancer-imaging
#20
Hui Liu, Yuxiang Han, Jiyuan Li, Ming Qin, Qunfeng Fu, Chunhong Wang, Zhibo Liu
Amino acids derivatives are well established molecular probes for diagnosis of a variety of cancer using positron emission tomography (PET). Recently, boramino acid (BAAs) was found as a prospective molecular platform for developing PET tracer. The objective of this study was to develop a 18F-labeled alanine derivative through displacing its carboxylate by trifluoroborate as a selective ASCT2 marker for cancer imaging. 18F-Ala-BF3 was firstly evaluated in healthy FVB/N mice in vivo, exhibiting rapid renal clearance with almost negligible uptake in stomach (1...
January 8, 2018: Molecular Pharmaceutics
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