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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/28409629/tuning-the-extent-and-depth-of-penetration-of-flexible-liposomes-in-human-skin
#1
Silvia Franzè, Giulia Donadoni, Alessandro Podestà, Patrizia Procacci, Marica Orioli, Marina Carini, Paola Minghetti, Francesco Cilurzo
In this work we made an attempt to assess the effect of drug-induced changes of flexibility on the penetration of deformable vesicles into the human skin. Eight cationic liposomes with different degrees of flexibility were obtained by entrapping unfractionated heparin, enoxaparin and nadroparin. The deformability was studied by a novel, facile and reliable extrusion assay appositely developed and validated by means of quantitative nanoscale mechanical AFM measurements of vesicle elastic modulus (log10(YM))...
April 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28035828/hepatic-carcinoma-selective-nucleic-acid-nanovector-assembled-by-endogenous-molecules-based-on-modular-strategy
#2
Fang Xie, Luchen Zhang, Jinliang Peng, Chong Li, Jun Pu, Yuhong Xu, Zixiu Du
We rationally formulated a nucleic acid nanovector platform utilizing endogenous molecules in the following steps: nucleic acids are initially packed by a multifunctional peptide and a cationic liposome to form positively charged ternary complexes through electrostatic interaction; then the ternary complexes were coated with hyaluronic acid (HA) to form negatively charged quaternary nanocomplexes (Q-complexes). Among the components of Q-complexes, the multifunctional peptide was composed of a poly-16-arginine (R16) and a hepatic tumor-targeted cell penetrating peptide (KRPTMRFRYTWNPMK); the cationic lipid component included DOTAP and fusogenic lipid DOPE; the HA component shielded the cationic ternary complexes and actively targeted the CD44 overexpressed on the surface of tumor cells...
April 24, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28426226/brain-uptake-of-bioactive-flavones-in-scutellariae-radix-and-its-relationship-to-anxiolytic-effect-in-mice
#3
Sophia Yui Kau Fong, Chenrui Li, Yiu Cheong Ho, Rui Li, Qian Wang, Yin Cheong Wong, Hong Xue, Zhong Zuo
Scutellariae Radix (SR) and its bioactive flavones elicit a variety of effects in the brain. However, the brain uptake of individual SR flavones and its relationship to the elicited effects after SR administration remain unknown. Moreover, previous studies seldom measured pharmacokinetic and pharmacodynamic outcomes simultaneously. In the current study, the brain uptake of six major SR flavones and the anxiolytic behavior following oral administration of a SR extract at two clinically relevant doses (600 and 1200 mg/kg twice daily) were simultaneously investigated in mice (n=18 per group)...
April 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28394617/understanding-the-impact-of-water-on-the-miscibility-and-microstructure-of-amorphous-solid-dispersions-an-afm-lcr-and-tem-edx-study
#4
Na Li, Christopher J Gilpin, Lynne S Taylor
Miscibility is critical for amorphous solid dispersions (ASDs). Phase-separated ASDs are more prone to crystallization, and thus can lose their solubility advantage leading to product failure. Additionally, dissolution performance can be diminished as a result of phase separation in the ASD matrix. Water is known to induce phase separation during storage for some ASDs. However, the impact of water introduced during preparation has not been as thoroughly investigated to date. The purpose of this study was to develop a mechanistic understanding of the effect of water on the phase behavior and microstructure of ASDs...
April 19, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28343398/an-anti-programmed-death-1-antibody-%C3%AE-pd-1-fusion-protein-that-self-assembles-into-a-multivalent-and-functional-%C3%AE-pd-1-nanoparticle
#5
Peng Zhao, Djordje Atanackovic, Shuyun Dong, Hideo Yagita, Xiao He, Mingnan Chen
Cancer immune checkpoint therapy has achieved remarkable clinical successes in various cancers. However, current immune checkpoint inhibitors block the checkpoint of not only the immune cells that are important to cancer therapy but also the immune cells that are irrelevant to the therapy. Such an indiscriminate blockade limits the efficacy and causes the autoimmune toxicity of the therapy. It might be beneficial to use a carrier to target immune checkpoint inhibitors to cancer-reactive immune cells. Here, we explore a method to load the inhibitors into carriers...
April 19, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28418683/physical-characterization-of-tobramycin-inhalation-powder-ii-state-diagram-of-an-amorphous-engineered-particle-formulation
#6
Dan Miller, Trixie Tan, John Nakamura, Richard Malcolmson, Tom Tarara, Jeff Weers
Tobramycin Inhalation Powder (TIP) is a spray-dried engineered particle formulation used in TOBI® Podhaler®, a drug/device combination for treatment of cystic fibrosis. A TIP particle consists of two phases: amorphous, glassy tobramycin sulfate and a gel-phase phospholipid (DSPC). The objective of this work was to characterize both the amorphous and gel phases following exposure of TIP to a broad range of relative humidity and temperature. Because, in principle, changes in either particle morphology or the solid-state form of the drug could affect drug delivery or biopharmaceutical properties, understanding physical stability was critical to development and registration of this product...
April 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28403609/solid-state-nmr-characterization-of-ibuprofen-nicotinamide-cocrystals-and-new-idea-for-controlling-release-of-drugs-embedded-into-mesoporous-silica-particles
#7
Ewa Skorupska, Sławomir Kaźmierski, Marek J Potrzebowski
Grinding and melting methods were employed for synthesis of pharmaceutical cocrystals formed by racemic (R/S) and entiomeric (S) ibuprofen (IBU) and nicotinamide (NA) as coformer. Obtained (R/S)-IBU:NA and (S)-IBU:NA cocrystals were fully characterized by means of advanced one- and two-dimensional solid state nuclear magnetic resonance (SS NMR) techniques with very fast magic angle spinning (MAS) at 60 kHz. The distinction in molecular packing and specific hydrogen bonding pattern was clearly recognized by analysis of (1)H, (13)C, and (15)N spectra...
April 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28410440/control-of-liposomal-penetration-into-three-dimensional-multicellular-tumor-spheroids-by-modulating-liposomal-membrane-rigidity
#8
Yuki Takechi-Haraya, Yukihiro Goda, Kumiko Sakai-Kato
Effective penetration of drug-carrying nanoparticles into solid tumors is a major challenge in cancer therapy. Exploration of the physicochemical properties of nanoparticles that affect penetration efficiency is required to achieve maximum therapeutic effects. Here, we used confocal laser scanning microscopy to evaluate the efficiencies of penetration of fluorescently-labeled liposomes into three-dimensional spheroids composed of HeLa cells. The prepared liposomes were composed of phosphatidylcholines and varying contents of cholesterol and/or a polyethylene glycol-modified phospholipid...
April 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28402673/functionalized-lipid-polymer-hybrid-nanoparticles-mediated-co-delivery-of-methotrexate-aceclofenac-a-synergistic-effect-in-breast-cancer-with-improved-pharmacokinetics-attributes
#9
Neeraj K Garg, Rajeev K Tyagi, Gajanand Sharma, Ashay Jain, Bhupinder Singh, Sanyog Jain, O P Katare
Present study was aimed to co-encapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid-polymer hybrid nanoparticles (Fu-LPHNPs) to achieving target specific and controlled delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires co-administration of drugs to achieving synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of co-delivery of MTX & ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231) to reduce the adverse effects...
April 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28388076/immunopet-imaging-of-ctla-4-expression-in-mouse-models-of-non-small-cell-lung-cancer
#10
Emily B Ehlerding, Christopher G England, Rebecca L Majewski, Hector F Valdovinos, Dawei Jiang, Glenn Liu, Douglas G McNeel, Robert J Nickles, Weibo Cai
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed on the surface of activated T cells and some tumor cells, and is the target of the clinically approved monoclonal antibody ipilimumab. In this study, we investigate specific binding of radiolabeled ipilimumab to CTLA-4 expressed by human non-small cell lung cancer cells in vivo using positron emission tomography (PET). Ipilimumab was radiolabeled with (64)Cu (t1/2 = 12.7 h) through the use of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to formulate (64)Cu-DOTA-ipilimumab...
April 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28358987/highly-selective-targeting-of-hepatic-stellate-cells-for-liver-fibrosis-treatment-using-a-d-enantiomeric-peptide-ligand-of-fn14-identified-by-mirror-image-mrna-display
#11
Luying Huang, Jing Xie, Qiuyan Bi, Zhuoxuan Li, Sha Liu, Qing Shen, Chong Li
Although liver fibrosis is a major public health issue, there is still no effective drug therapy in the clinic. Fibroblast growth factor-inducible 14 (Fn14), a membrane receptor highly specifically expressed in activated hepatic stellate cells (HSCs), is the key driver of liver fibrosis, and thus, it has a great potential as a novel target for the development of effective treatment. Here, we identified a d-enantiomeric peptide ligand of Fn14 through mirror-image mRNA display. This included the chemical synthesis of a d-enantiomer of the target protein (extracellular domain of Fn14), identification of an l-peptide ligand of d-Fn14 using a constructed mRNA peptide library, and identification of a d-enantiomer of the l-peptide, which is a ligand of the natural Fn14 for reasons of symmetry...
April 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28355489/encapsulation-of-ibuprofen-in-cd-mof-and-related-bioavailability-studies
#12
Karel J Hartlieb, Daniel P Ferris, James M Holcroft, Irawati Kandela, Charlotte L Stern, Majed S Nassar, Youssry Y Botros, J Fraser Stoddart
Although ibuprofen is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs), it exhibits poor solubility in aqueous and physiological environments as a free acid. In order to improve its oral bioavailability and rate of uptake, extensive research into the development of new formulations of ibuprofen has been undertaken, including the use of excipients as well as ibuprofen salts, such as ibuprofen lysinate and ibuprofen, sodium salt. The ultimate goals of these studies are to reduce the time required for maximum uptake of ibuprofen, as this period of time is directly proportional to the rate of onset of analgesic/anti-inflammatory effects, and to increase the half-life of the drug within the body; that is, the duration of action of the effects of the drug...
April 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28368124/development-of-surface-variable-polymeric-nanoparticles-for-drug-delivery-to-tumors
#13
Ning Han, Liang Pang, Jun Xu, Hyesun Hyun, Jinho Park, Yoon Yeo
To develop nanoparticle drug carriers that interact with cells specifically in the mildly acidic tumor microenvironment, we produced polymeric nanoparticles modified with amidated TAT peptide via a simple surface modification method. Two types of core poly(lactic-co-glycolic acid) nanoparticles (NL and NP) were prepared with a phospholipid shell as an optional feature and covered with polydopamine that enabled the conjugation of TAT peptide on the surface. Subsequent treatment with acid anhydrides such as cis-aconitic anhydride (CA) and succinic anhydride (SA) converted amines of lysine residues in TAT peptide to β-carboxylic amides, introducing carboxylic groups that undergo pH-dependent protonation and deprotonation...
April 11, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28363028/spectroscopic-investigation-of-the-formation-and-disruption-of-hydrogen-bonds-in-pharmaceutical-semicrystalline-dispersions
#14
Tu Van Duong, Gunter Reekmans, Akkaladevi Venkatesham, Arthur Van Aerschot, Peter Adriaensens, Jan Van Humbeeck, Guy Van den Mooter
We recently found that indomethacin (IMC) can effectively act as a powerful crystallization inhibitor for polyethylene glycol 6000 (PEG) despite the fact that the absence of interactions between the drug and the carrier in the solid state was reported in the literature. However, in the present study, we investigate the possibility of drug-carrier interactions in the liquid state to explain the polymer crystallization inhibition effect of IMC. We also aim to discover other potential PEG crystallization inhibitors...
April 11, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28394618/potential-eye-drop-based-on-a-calix-4-arene-nanoassembly-for-curcumin-delivery-enhanced-drug-solubility-stability-and-anti-inflammatory-effect
#15
Giuseppe Granata, Irene Paterniti, Corrada Geraci, Francesca Cunsolo, Emanuela Esposito, Marika Cordaro, Anna Rita Blanco, Salvatore Cuzzocrea, Grazia M L Consoli
Curcumin is an Indian spice with a wide spectrum of biological and pharmacological activities but poor aqueous solubility, rapid degradation, and low bioavailability that affect medical benefits. To overcome these limits in ophthalmic application, curcumin was entrapped in a polycationic calix[4]arene-based nanoaggregate by a simple and reproducible method. The calix[4]arene-curcumin supramolecular assembly (Calix-Cur) appeared as a clear colloidal solution consisting in micellar nanoaggregates with size, polydispersity index, surface potential, and drug loading percentage meeting the requirements for an ocular drug delivery system...
April 10, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28394614/a-synthetic-macromolecular-antibiotic-platform-for-inhalable-therapy-against-aerosolized-intracellular-alveolar-infections
#16
Debobrato Das, Jasmin Chen, Selvi Srinivasan, Abby Michelle Kelly, Brian Lee, Hye-Nam Son, Frank Radella, Timothy E West, Daniel M Ratner, Anthony J Convertine, Shawn J Skerrett, Patrick S Stayton
Lung-based intracellular bacterial infections remain one of the most challenging infectious disease settings. For example, the current standard for treating Franciscella tularensis pneumonia (tularemia) relies on prolonged administration of oral and intravenous antibiotics that poorly achieve and sustain pulmonary drug bioavailability. Inhalable antibiotic formulations are approved and in clinical development for upper respiratory infections, but sustained drug dosing from inhaled antibiotics against alveolar intracellular infections remains a current unmet need...
April 10, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28388081/ingr-modified-liposomes-for-tumor-vascular-targeting-and-tumor-tissue-penetrating-delivery-in-the-treatment-of-glioblastoma
#17
Jing-E Zhou, Jing Yu, Lipeng Gao, Lei Sun, Ting Peng, Jing Wang, Jianzhong Zhu, Weiyue Lu, Lin Zhang, Zhiqiang Yan, Lei Yu
The tumor vascular barrier and tumor stroma barrier become the two main obstacles in the in vivo delivery of nanomedicines. In this study, to overcome the two barriers, we used iNGR, a tumor-penetrating peptide, to modify the liposomes to increase their accumulation and penetration in tumor tissues. Firstly, iNGR-modified sterically stabilized liposomes (iNGR-SSL) were prepared, which showed vesicle sizes of about 100 nm and narrow size distribution. The uptake of iNGR-SSL by U87MG cells and HUVECs were significantly more than that of unmodified liposome...
April 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28345929/utility-of-cyp3a4-and-pxr-car-cyp3a4-3a7-transgenic-mouse-models-to-assess-the-magnitude-of-cyp3a4-mediated-drug-drug-interactions
#18
Justin Q Ly, Kirsten Messick, Ann Qin, Ryan H Takahashi, Edna F Choo
Species differences in the expression, activity, regulation, and substrate specificity of metabolizing enzymes preclude the use of animal models to predict clinical drug-drug interactions (DDIs). The objective of this work is to determine if the transgenic (Tg) Cyp3a(-/-)Tg-3A4Hep/Int and Nr1i2/Nr1i3(-/-)-Cyp3a(-/-)Tg-PXR-CAR-3A4/3A7Hep/Int (PXR-CAR-CYP3A4/3A7) mouse models could be used to predict in vivo DDI of 10 drugs; alprazolam, bosutinib, crizotinib, dasatinib, gefitinib, ibrutinib, regorafenib, sorafenib, triazolam, and vandetinib (as victims); with varying magnitudes of reported CYP3A4 clinical DDI...
April 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28350966/cationic-phosphorus-dendrimer-enhances-photodynamic-activity-of-rose-bengal-against-basal-cell-carcinoma-cell-lines
#19
Monika Dabrzalska, Anna Janaszewska, Maria Zablocka, Serge Mignani, Jean Pierre Majoral, Barbara Klajnert-Maculewicz
In the last couple of decades, photodynamic therapy emerged as a useful tool in the treatment of basal cell carcinoma. However, it still meets limitations due to unfavorable properties of photosensitizers such as poor solubility or lack of selectivity. Dendrimers, polymers widely studied in biomedical field, may play a role as photosensitizer carriers and improve the efficacy of photodynamic treatment. Here, we describe the evaluation of an electrostatic complex of cationic phosphorus dendrimer and rose bengal in such aspects as singlet oxygen production, cellular uptake, and phototoxicity against three basal cell carcinoma cell lines...
April 6, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28380300/biophysical-study-on-the-interaction-between-eperisone-hydrochloride-and-human-serum-albumin-using-spectroscopic-calorimetric-and-molecular-docking-analysis
#20
Gulam Rabbani, Mohammad Hassan Baig, Eun Ju Lee, Won Kyung Cho, Jin Yeul Ma, Inho Choi
Eperisone hydrochloride (EH) is a widely used as a muscle relaxant for patients with muscular contracture, low back pain, or spasticity. Human serum albumin (HSA), a highly soluble negatively charged, endogenous and abundant plasma protein ascribed with the ligand binding and transport properties. The current study was undertaken to explore the interaction between EH and the serum transport protein, HSA. Study of the interaction between HSA and EH was carried by UV-vis, fluorescence quenching, circular dichroism (CD) spectroscopy, FRET, and ITC...
April 5, 2017: Molecular Pharmaceutics
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