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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/29782805/maintaining-supersaturation-of-nimodipine-by-pvp-with-or-without-the-presence-of-sodium-lauryl-sulfate-and-sodium-taurocholate
#1
Yipshu Pui, Yuejie Chen, Huijun Chen, Shan Wang, Chengyu Liu, Wouter Tonnis, Linc Chen, Peter Serno, Stefan Bracht, Feng Qian
Amorphous solid dispersion (ASD) is one of the most versatile supersaturating drug delivery system to improve the dissolution rate and oral bioavailability of poorly water soluble drugs. PVP based ASD formulation of nimodipine (NMD) has been marketed and effectively used in clinic for nearly 30 years, yet the mechanism by which PVP maintains the supersaturation and subsequently improves the bioavailability of NMD was rarely investigated. In this research, we first studied the molecular interactions between NMD and PVP by solution NMR using CDCl3 as the solvent, and drug-polymer Flory-Huggins interaction parameter...
May 21, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29782803/amphiphilic-hybrid-dendritic-linear-molecules-as-nanocarriers-for-shape-dependent-antitumor-drug-delivery
#2
Yifei Guo, Ting Wang, Shuang Zhao, Meihua Han, Zhengqi Dong, Xiangtao Wang, Yanhong Wang
Nanoparticles based on hybrid block copolymers had been expected as effective nanocarriers for hydrophobic drug delivery. Herein, the novel dendritic-linear molecules from OEG dendron conjugated with octadecylamine (G2-C18) was designed, synthesized and further applied as nanocarrier to prepare 10-hydroxycamptothecin (HCPT) nanoparticles via antisolvent precipitation method. It seemed that the feed weight ratio of HCPT vs. G2-C18 not only affected the drug-loading content of nanoparticles, but also influenced the morphology of HCPT nanoparticles, the morphology of HCPT nanoparticles was changed from nanosphere (NSs) to nanorod (NRs) with increasing the feed weight ratio...
May 21, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29782174/expression-of-concentrative-nucleoside-transporters-slc28a-in-the-human-placenta-effects-of-gestation-age-and-prototype-differentiation-affecting-agents
#3
Lucie Jiraskova, Lukas Cerveny, Sara Karbanova, Zuzana Ptackova, Frantisek Staud
Equilibrative ( SLC29A) and concentrative ( SLC28A) nucleoside transporters contribute to proper placental development and mediate uptake of nucleosides/nucleoside-derived drugs. We analyzed placental expression of SLC28A mRNA during gestation. Moreover, we studied in choriocarcinoma-derived BeWo cells whether SLC29A and SLC28A mRNA levels can be modulated by activity of adenylyl cyclase, retinoic acid receptor activation, CpG islands methylation, or histone acetylation, using forskolin, all- trans-retinoic acid, and 5-azacytidine, and sodium butyrate/sodium valproate, respectively...
May 21, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29775322/prediction-of-human-cytochrome-p450-inhibition-using-a-multi-task-deep-autoencoder-neural-network
#4
Xiang Li, Youjun Xu, Luhua Lai, Jianfeng Pei
Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP450) inhibition is an important consideration in drug discovery. It is highly desirable to develop computational models that can predict the inhibitive effect of a compound against a specific CYP450 isoform. In this study, we developed a multi-task model for concurrent inhibition prediction of five major CYP450 isoforms, namely 1A2, 2C9, 2C19, 2D6, and 3A4. The model was built by training multi-task autoencoder deep neural network (DNN) on a large dataset containing more than 13000 compounds, extracted from PubChem BioAssay Database...
May 18, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29771534/nitroxyl-modified-tobacco-mosaic-virus-as-a-metal-free-high-relaxivity-mri-and-epr-active-superoxide-sensor
#5
Madushani Dharmarwardana, Andre F Martins, Zhuo Chen, Philip Palacios, Chance M Nowak, Raymond P Welch, Shaobo Li, Michael Andrew Luzuriaga, Leonidas Bleris, Brad S Pierce, A Dean Sherry, Jeremiah J Gassensmith
Superoxide overproduction is known to occur in multiple disease states requiring critical care yet non-invasive detection of superoxide in deep tissue remains a challenge. Herein, we report a metal-free magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) active contrast agent prepared by "click conjugating" paramagnetic organic radical contrast agents (ORCAs) to the surface of tobacco mosaic virus (TMV). While ORCAs are known to be reduced in vivo to an MRI/EPR silent state, their oxidation is facilitated specifically by reactive oxygen species-in particular superoxide-and are largely unaffected by peroxides and molecular oxygen...
May 17, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29771531/exosomes-as-a-drug-delivery-system-in-cancer-therapy-potential-and-challenges
#6
Golam Kibria, Erika Kathryn Ramos, David R Gius, Yong Wan, Huiping Liu
Exosomes play a pivotal role in mediating intercellular communications and package delivery. They have recently been discovered to serve as diagnostic biomarkers as well as a possible drug delivery vehicle based on their nanometer size range and capability to transfer biological materials to recipient cells. Their unique biocompatibility, high stability, preferred tumor homing, and adjustable targeting efficiency can make exosomes an attractive and potentially effective tool of drug delivery in cancer therapy...
May 17, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29768014/hybrid-mesoporous-microporous-nanocarriers-for-overcoming-multidrug-resistance-by-sequential-drug-delivery
#7
Liucan Wang, Haidi Guan, Zhenqiang Wang, Yuxin Xing, Jixi Zhang, Kaiyong Cai
Combination chemotherapy with a modulator and a chemotherapeutic drug has become one of the most promising strategies for the treatment of multidrug resistance (MDR) in cancer therapy. However, the development of nanocarriers with a high payload and sequential release of therapeutic agents poses a significant challenge. In this work, we report a type of hybrid nanocarriers prepared by polydopamine (PDA) mediated integration of the mesoporous MSN core and the microporous zeolite imidazolate frameworks-8 (ZIF-8) shell...
May 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29768009/use-of-dual-ligand-modification-in-kupffer-cell-targeted-liposomes-to-examine-the-contribution-of-kupffer-cells-to-accelerated-blood-clearance-abc-phenomenon
#8
Chaoyang Lai, Cong Li, Xiang Luo, Mengyang Liu, Xinrong Liu, Ling Hu, Le Kang, Qiujun Qiu, Yihui Deng, Yanzhi Song
The "accelerated blood clearance (ABC) phenomenon" is known to be involved in the adaptive immune system. Regretfully, the relationship between the ABC phenomenon and innate immune system, especially with respect to Kupffer cells (KCs) has been largely unexplored. In this study, the contribution of KCs to ABC was examined using the 4-aminophenyl-α-D-mannopyranoside (APM) lipid derivative DSPE-PEG2000-APM (DPM) and the 4-aminophenyl-β-L-fucopyranoside (APF) lipid derivative DSPE-PEG2000-APF (DPF) as ligands for mannose/fucose receptors on KCs, which were synthesized and modified on the surface of liposomes...
May 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29767984/digesting-a-path-forward-the-utility-of-collagenase-tumor-treatment-for-improved-drug-delivery
#9
Aaron Dolor, Francis C Szoka
Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment...
May 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29767982/dentimol-as-a-dendrimeric-timolol-analogue-for-glaucoma-therapy-synthesis-and-preliminary-efficacy-and-safety-assessment
#10
Michael G Lancina, Juan Wang, Geoffrey S Williamson, Hu Yang
In this work, we report synthesis and characterization of DenTimol, a dendrimer-based polymeric timolol analog as glaucoma medication. A timolol precursor (S)-4-[4-(oxiranylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine (OTM) was reacted with the heterobifunctional amine polyethylene glycol acetic acid (Amine-PEG-Acetic Acid, Mn=2000 g/mol) via the ring opening reaction of epoxide by an amine to form OTM-PEG conjugate. OTM-PEG was then coupled to ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimer G3 to generate DenTimol using the N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) coupling reaction...
May 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29767978/dynamics-of-ionic-liquids-assisted-refolding-of-denatured-cytochrome-c-a-study-of-preferential-interactions-towards-renaturation
#11
Upendra Kumar Singh, Rajan Patel
In vitro refolding of denatured proteins and influence of alkyl chain of these organic salts on their performance as refolding enhancers was tested using long chain imidazolium chloride salts, 1-methyl-3-octylimidazolium chloride [C8mim][Cl], 1-decyl-3-methylimidazolium chloride [C10mim][Cl]. The horse heart cytochrome c (h-cyt c) was denatured by urea and guanidinium hydrochloride (GdnHCl), as well as base induced denaturation at pH 13 to provide a broad overview of the overall refolding behavior. The variation in alkyl chain of ionic liquids (ILs) showed a profound effect on the refolding of denatured h-cyt c...
May 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29764120/multi-arm-nanoconjugates-for-cancer-cell-targeted-delivery-of-photosensitizers
#12
Yan Zhao, Fang Li, Chengqiong Mao, Xin Ming
Photodynamic therapy, a procedure that uses a photosensitizer to enable light therapy selectively at diseased sites, remains underutilized in oncological clinic. To further improve its cancer selectivity, we developed a polymeric nanosystem by conjugating a photosensitizer IRDye 700DX (IR700) and cancer targeting RGD peptide to 8-arm polyethylene glycol (PEG). The resulting nanoconjugates (RGD-8PEG-IR700) exhibited a hydrodynamic size of 6.6 nm with narrow distribution of size. The targeted nanoconjugates showed significantly higher intracellular uptake of IR700 in integrin αvβ3-expressing A375 and SKOV3 cells when compared with non-targeted control 8PEG-IR700, and excess amount of RGD peptides could abolish this enhancement, indicating a receptor-medicated uptake mechanism for the targeted polymer conjugates...
May 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29763568/near-infrared-activatable-phthalocyanine-poly-l-glutamic-acid-conjugate-enhanced-in-vivo-safety-and-antitumor-efficacy-towards-an-effective-photodynamic-cancer-therapy
#13
Hoay Yan Cheah, Elena Gallon, Fabienne Dumoulin, See Ziau Hoe, Nina Japundžić-Žigon, Sofija Glumac, Hong Boon Lee, Prem Anand, Lip Yong Chung, Maria Jesus Vicent, Lik Voon Kiew
We previously developed a new zinc (II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity and non-selectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near infrared (NIR) light absorptivity (λmax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro...
May 15, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29763559/long-acting-release-microspheres-containing-novel-glp-1-analog-as-an-antidiabetic-system
#14
Sida Ruan, Yuanyuan Gu, Bo Liu, Huashan Gao, Xiongwei Hu, Haiping Hao, Liang Jin, Ting Cai
Glucagon-like peptide 1 (GLP-1) has recently received significant attention as an efficacious way to treat diabetes mellitus. However, the short half-life of the peptide limits its clinical application in diabetes. In our previous study, a novel GLP-1 analog (PGLP-1) with a longer half-life was synthesized and evaluated. Herein, we prepared the PGLP-1-loaded poly(D,L-lactide-co- glycolide) microspheres to achieve long-term effects on blood glucose control. The incorporation of zinc ion into the formulation can effectively decrease the initial burst release, and a uniform drug distribution was obtained, in contrast to native PGLP-1 encapsulated microspheres...
May 15, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29763553/effective-remodelling-of-human-osteoarthritic-cartilage-by-sox9-gene-transfer-and-overexpression-upon-delivery-of-raav-vectors-in-polymeric-micelles
#15
Ana Rey-Rico, Jagadesh Kumar Venkatesan, Gertrud Schmitt, Susanne Speicher-Mentges, Henning Madry, Magali Cucchiarini
Recombinant adeno-associated virus (rAAV) vectors are well suited carriers to provide durable treatments for human osteoarthritis (OA). Controlled release of rAAV from polymeric micelles was already shown to increase both the stability and bioactivity of the vectors while overcoming barriers precluding effective gene transfer. In the present study, we examined the convenience of delivering rAAV vectors via poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) polymeric (PEO-PPO-PEO) micelles to transfer and overexpress the transcription factor SOX9 in monolayers of human OA chondrocytes and in experimentally created human osteochondral defects...
May 15, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29763317/chemoproteomic-profiling-reveals-ethacrynic-acid-targets-adenine-nucleotide-translocases-to-impair-mitochondrial-function
#16
Zi Ye, Xiaoyun Zhang, Yuangang Zhu, Tong Song, Xiaowei Chen, Xiaoguang Lei, Chu Wang
Ethacrynic acid (EA) is a diuretic drug that is widely used to treat high-blood pressure and swelling caused by congestive heart failure or kidney failure. It acts through noncovalent inhibition of the Na+ -K+ -2Cl- cotransporter in the thick ascending limb of Henle's loop. Chemically, EA contains a Michael acceptor group that can react covalently with nucleophilic residues in proteins; however, the proteome reactivity of EA remains unexplored. Herein, we took a quantitative chemoproteomic approach to globally profile EA's targets in cancer cells...
May 15, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29762040/orally-bioavailable-and-effective-buparvaquone-lipid-based-nanomedicines-for-visceral-leishmaniasis
#17
Lindsay A Smith, Dolores Remedios Serrano, Marion Mauger, Francisco Bolás-Fernández, Maria Auxiliadora Dea-Ayuela, Aikaterini Lalatsa
Nano-enabled lipid based drug delivery systems offer a platform to overcome challenges encountered with current failed leads in the treatment of parasitic and infectious diseases. When prepared with FDA or EMA approved excipients, they can be readily translated without the need for further toxicological studies, while they remain affordable and amenable to scale-up. Buparvaquone (BPQ), a hydroxynapthoquinone with in vitro activity in the nanomolar range, failed to clinically translate as a viable treatment for visceral leishmaniasis due to its poor oral bioavailability limited by its poor aqueous solubility (BCS Class II drug)...
May 15, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29762034/ionic-liquid-based-paclitaxel-preparation-a-new-potential-formulation-for-cancer-treatment
#18
Chowdhury Md Raihan, Rahman Md Moshikur, Rie Wakabayashi, Yoshiro Tahara, Noriho Kamiya, Muhammad Moniruzzaman, Masahiro Goto
Paclitaxel (PTX) injection (i.e. Taxol) has been used as an effective chemotherapeutic treatment for various cancers. However, the current Taxol formulation contains Cremophor EL, which causes hypersensitivity reactions during intravenous administration and precipitation by aqueous dilution. This article reports the preliminary results on the ionic liquid (IL)-based PTX formulations developed to address the aforementioned issues. The formulations were composed of PTX/cholinium amino acid ILs/ethanol/tween-80/water...
May 15, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29757659/bone-marrow-derived-mesenchymal-stem-cells-promoted-cutaneous-wound-healing-by-regulating-keratinocyte-migration-via-the-%C3%AE-2-adrenergic-receptor-signaling
#19
Jiahui Huo, Sujing Sun, Zhijun Geng, Wei Sheng, Runkai Chen, Kui Ma, Xiaoyan Sun, Xiaobing Fu
Mesenchymal stem cells (MSCs) play an important role in the cutaneous wound healing; however, the functional mechanisms involved in the healing process are poorly understood. A series of studies indicate that keratinocytes which migrate into the wound bed rely on an epithelial-mesenchymal transition (EMT)-like process to initiate re-epithelialization. We therefore examined whether bone marrow-derived MSCs (BMSCs) could affect biological behavior and induce EMT-like characteristics in the human epidermal keratinocytes (HEKs) and in the immortalized human keratinocyte cell line HaCaT cells; and we investigated the signaling pathways of BMSC-mediated phenotypic changes...
May 14, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29757658/a-macropinocytosis-intensifying-albumin-domain-based-scfv-antibody-and-its-conjugate-directed-against-k-ras-mutant-pancreatic-cancer
#20
Xiaofei Wang, Weijin Sheng, Yangyang Wang, Liang Li, Yi Li, Shenghua Zhang, Xiujun Liu, Shuzhen Chen, Yongsu Zhen
Enhanced macropinocytosis has been found in K-Ras mutant pancreatic cancer cells and through which albumin can massively enter into the K-Ras driven cancer cells suggesting its role serving as micropinocytosis-intensifying drug delivery carrier. In the present study, a novel recombinant protein Fv-LDP-D3 and its reconstituted analogue Fv-LDP-D3-AE were designed and prepared. In which, Fv is the fragment of an anti-EGFR antibody, D3 is the domain III of HSA, LDP is the apoprotein of the antitumor antibiotic lidamycin (LDM), and AE is an extremely cytotoxic enediyne derived from LDM...
May 14, 2018: Molecular Pharmaceutics
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