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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/28636400/click-biotinylation-of-plga-template-for-biotin-receptor-oriented-delivery-of-doxorubicin-hydrochloride-in-4t1-cell-induced-breast-cancer
#1
Yuvraj Singh, K K Durga Rao Viswanadham, Arun Kumar Jajoriya, Jayagopal Meher, Kavit Raval, Swati Jaiswal, Jayant Dewangan, H K Bora, Srikanta Kumar Rath, Jawahar Lal, Durga Prasad Mishra, Manish Kumar Chourasia
PLGA was functionalized with PEG and biotin using click chemistry to generate a biotin receptor targeted copolymer (Biotinylated-PEG-PLGA) which in turn was used to fabricate ultrafine nanoparticles (BPNP) of doxorubicin hydrochloride (DOX) for effective delivery in 4T1 cell induced breast cancer. However adequate entrapment of a hydrophilic bioactive like DOX in a hydrophobic polymer system made of PLGA is not usually possible. We therefore modified a conventional W/O/W emulsion method by utilizing ammonium chloride in the external phase to constrain DOX in dissolved polymer phase by supressing its inherent aqueous solubility as per common ion effect...
June 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28595388/admet-evaluation-in-drug-discovery-part-17-development-of-quantitative-and-qualitative-prediction-models-for-chemical-induced-respiratory-toxicity
#2
Tailong Lei, Fu Chen, Hui Liu, Huiyong Sun, Yu Kang, Dan Li, Youyong Li, Tingjun Hou
As a dangerous end point, respiratory toxicity can cause serious adverse health effects and even death. Meanwhile, it is a common and traditional issue in occupational and environmental protection. Pharmaceutical and chemical industries have a strong urge to develop precise and convenient computational tools to evaluate the respiratory toxicity of compounds as early as possible. Most of the reported theoretical models were developed based on the respiratory toxicity data sets with one single symptom, such as respiratory sensitization, and therefore these models may not afford reliable predictions for toxic compounds with other respiratory symptoms, such as pneumonia or rhinitis...
June 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28505457/molecular-and-biocompatibility-characterization-of-red-blood-cell-membrane-targeted-and-cell-penetrating-peptide-modified-polymeric-nanoparticles
#3
Kaustuv Sahoo, Sriharsha Karumuri, Rangika S Hikkaduwa Koralege, Nicholas H Flynn, Steve Hartson, Jing Liu, Joshua D Ramsey, A Kaan Kalkan, Carey Pope, Ashish Ranjan
Red blood cells (RBCs) express a variety of immunomodulatory markers that enable the body to recognize them as self. We have shown that RBC membrane glycophorin A (GPA) receptor can mediate membrane attachment of protein therapeutics. A critical knowledge gap is whether attaching drug-encapsulated nanoparticles (NPs) to GPA and modification with cell-penetrating peptide (CPP) will impact binding, oxygenation, and the induction of cellular stress. The objective of this study was to formulate copolymer-based NPs containing model fluorescent-tagged bovine serum albumin (BSA) with GPA-specific targeting ligands such as ERY1 (ENPs), single-chain variable antibody (scFv TER-119, SNPs), and low-molecular-weight protamine-based CPP (LNPs) and to determine their biocompatibility using a variety of complementary high-throughput in vitro assays...
June 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28631484/ocular-pharmacokinetics-of-therapeutic-antibodies-given-by-intravitreal-injection-estimation-of-retinal-permeabilities-using-a-3-compartment-semi-mechanistic-model
#4
Laurence A Hutton-Smith, Eamonn A Gaffney, Helen M Byrne, Philip K Maini, Kapil Gadkar, Norman Alan Mazer
Intravitreally (IVT) injected macromolecules for the treatment of age-related macular degeneration must permeate through the inner limiting membrane (ILM) into the retina and through the retinal pigment epithelium (RPE) to enter the choroid. A quantitative understanding of intraocular transport mechanisms, elimination pathways and the effect of molecular size, is currently incomplete. We present a semi-mechanistic, 3-compartment (retina, vitreous and aqueous) pharmacokinetic (PK) model, expressed using linear ordinary differential equations (ODEs), to describe the molecular concentrations following a single IVT injection...
June 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28597653/overexpression-of-atp-binding-cassette-subfamily-g-member-2-confers-resistance-to-phosphatidylinositol-3-kinase-inhibitor-pf-4989216-in-cancer-cells
#5
Chung-Pu Wu, Megumi Murakami, Sung-Han Hsiao, An-Wei Chou, Yan-Qing Li, Yang-Hui Huang, Tai-Ho Hung, Suresh V Ambudkar
Deregulated activation of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently found in human cancers, which plays a key role in promoting cancer proliferation and resistance to anticancer therapies. Therefore, developing inhibitors targeting key components of the PI3K/Akt/mTOR signaling pathway has great clinical significance. PF-4989216 is a novel, orally available small-molecule drug that was developed to selectively inhibit the PI3K/Akt/mTOR signaling pathway and subsequent cancer cell proliferation...
June 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28597662/chitosan-hyaluronic-acid-nanoparticles-rational-design-revisited-for-rna-delivery
#6
Enrique Lallana, Julio M Rios de la Rosa, Annalisa Tirella, Maria Pelliccia, Arianna Gennari, Ian J Stratford, Sanyogitta Puri, Marianne Ashford, Nicola Tirelli
Chitosan/hyaluronic acid (HA) nanoparticles can be used to deliver an RNA/DNA cargo to cells overexpressing HA receptors such as CD44. For these systems, unequivocal links have not been established yet between chitosan macromolecular (molecular weight; degree of deacetylation, i.e., charge density) and nanoparticle variables (complexation strength, i.e., stability; nucleic acid protection; internalization rate) on one hand, and transfection efficiency on the other hand. Here, we have focused on the role of avidity on transfection efficiency in the CD44-expressing HCT-116 as a cellular model; we have employed two differently sized payloads (a large luciferase-encoding mRNA and a much smaller anti-Luc siRNA), and a small library of chitosans (variable molecular weight and degree of deactylation)...
June 19, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28621952/gastrointestinal-and-systemic-disposition-of-diclofenac-under-fasted-and-fed-state-conditions-supporting-the-evaluation-of-in-vitro-predictive-tools
#7
Jens Van Den Abeele, Ronald Schilderink, FElix Schneider, Raf Mols, Mans Minekus, Werner Weitschies, Joachim Brouwers, Jan Tack, Patrick Augustijns
This study aimed to gain further insight into the gastrointestinal disposition of the weakly acidic BCS Class II drug diclofenac and the implications for systemic drug exposure in humans under fasted and fed state conditions. For this purpose, gastrointestinal and blood samples were collected from healthy volunteers after oral intake of a commercially available tablet of the potassium salt of diclofenac (i.e. Cataflam®) in different prandial states. Subsequently, these in vivo data served as a reference for the evaluation of in vitro tools with different levels of complexity, i...
June 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28595387/delivery-of-cisplatin-anti-cancer-drug-from-carbon-boron-nitride-and-silicon-carbide-nanotubes-forced-by-ag-nanowire-a-comprehensive-molecular-dynamics-study
#8
Esmat Mehrjouei, Hamed Akbarzadeh, Amir Nasser Shamkhali, Mohsen Abbaspour, Sirous Salemi, Pooya Abdi
In this work, liberation of cisplatin molecules from interior of a nanotube due to entrance of an Ag-nanowire inside it was simulated by classical molecular dynamics method. The aim of this simulation was investigation on the effects of diameter, chirality, and composition of the nanotube, as well as the influence of temperature on this process. For this purpose, single walled carbon, boron nitride, and silicon carbide nanotube were considered. In order for a more concise comparison of the results, a new parameter namely efficiency of drug release, was introduced...
June 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28614662/investigating-liquid-liquid-phase-separation-of-a-monoclonal-antibody-using-solution-state-nmr-spectroscopy-effect-of-arg%C3%A2-glu-and-arg%C3%A2-hcl
#9
Priscilla Kheddo, Jack E Bramham, Rebecca J Dearman, Shahid Uddin, Christopher F van der Walle, Alexander P Golovanov
Liquid-liquid phase separation (LLPS) of monoclonal antibody (mAb) formulations involves spontaneous separation into dense (protein-rich) and diluted (protein-lean) phases, and should be avoided in the final drug product. Understanding the factors leading to LLPS, and ways to predict and prevent it would therefore be highly beneficial. Here we describe the link between LLPS behavior of an IgG1 mAb ('mAb5'), its solubility and parameters extracted using (1)H NMR spectroscopy, for various formulations. We show that the formulations demonstrating least LLPS lead to the largest mAb5 NMR signal intensities...
June 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28605595/efficient-co-delivery-of-paclitaxel-and-curcumin-by-novel-bottlebrush-copolymer-based-micelles
#10
Qing Yao, David C Gutierrez, Ngoc Ha Hoang, Dongin Kim, Ruoning Wang, Christopher Hobbs, Lin Zhu
The novel self-assembling bottlebrush polyethylene glycol - polynorbornene - thiocresol block copolymers (PEG-PNB-TC) were synthesized by the Ring Opening Metathesis Polymerization (ROMP), followed by functionalization of the polymer backbone via the thio-bromo "Click" post-polymerization strategy. The PEG-PNB-TC copolymers could easily self-assemble into the nanoscale core-shell polymeric micelles. The hydrophobic anticancer drugs, such as paclitaxel (PTX), could be loaded into their hydrophobic core to form a stable drug-loaded micelle with a superior drug loading capacity of up to ~ 35 % (wt/wt)...
June 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28603997/inhibition-of-human-ugt1a1-mediated-bilirubin-glucuronidation-by-polyphenolic-acids-impact-safety-of-popular-salvianolic-acid-a-b-containing-drugs-and-herbal-products
#11
Guo Ma, Ying Zhang, Wenyan Chen, Zhifang Tang, Xiaoming Xin, Ping Yang, Xiaoqin Liu, Weimin Cai, Ming Hu
Bilirubin-related adverse reactions (ADR, e.g., jaundice and hyperbilirubinemia) induced by herbs rich in certain polyphenolic acids are widely reported. However, the causes and the mechanisms underlying these ADR are not well understood. The purpose of this paper was to determine the mechanism by which certain polyphenolic acids inhibit UGT1A1-mediated bilirubin glucuronidation, leading to jaundice or hyperbilirubinemia. We investigated in vitro inhibitory effects on bilirubin glucuronidation of salvianolic acid A (SAA), salvianolic acid B (SAB), danshensu (DSS), protocatechuic aldehyde (PA) and rosmarinic acid (RA), as well as two Salvia miltiorrhiza injections (DSI and CDI) rich in polyphenolic acids...
June 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28570079/amorphous-polymeric-drug-salts-as-ionic-solid-dispersion-forms-of-ciprofloxacin
#12
Hanah Mesallati, Anita Umerska, Krzysztof J Paluch, Lidia Tajber
Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA)...
June 9, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28573863/cd38-as-a-pet-imaging-target-in-lung-cancer
#13
Emily B Ehlerding, Christopher G England, Dawei Jiang, Stephen A Graves, Lei Kang, Saige Lacognata, Todd E Barnhart, Weibo Cai
Daratumumab (Darzalex, Janssen Biotech) is a clinically approved antibody targeting CD38 for the treatment of multiple myeloma. However, CD38 is also expressed by other cancer cell types, including lung cancer, where its expression or absence may offer prognostic value. We therefore developed a PET tracer based upon daratumumab for tracking CD38 expression, utilizing murine models of non-small cell lung cancer to verify its specificity. Daratumumab was prepared for radiolabeling with (89)Zr (t1/2 = 78.4 h) through conjugation with desferrioxamine (Df)...
June 8, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28570823/formulation-of-nonionic-surfactant-vesicles-nisv-prepared-by-microfluidics-for-therapeutic-delivery-of-sirna-into-cancer-cells
#14
Mohammad A Obeid, Ashref Elburi, Louise C Young, Alexander B Mullen, Rothwelle J Tate, Valerie A Ferro
Small interfering RNAs (siRNA) have a broad potential as therapeutic agents to reversibly silence any target gene of interest. The clinical application of siRNA requires the use of safe and effective delivery systems. In this study, we investigated the use of nonionic surfactant vesicles (NISV) for the delivery of siRNA. Different types of NISV formulations were synthesized by microfluidic mixing and then evaluated for their physiochemical properties and cytotoxicity. The ability of the NISV to carry and transfect siRNA targeting green fluorescent protein (GFP) into A549 that stably express GFP (copGFP-A549) was evaluated...
June 8, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28505463/in-vivo-pretargeted-imaging-of-her2-and-tag-72-expression-using-the-halotag-enzyme
#15
James C Knight, Michael Mosley, H Tetsuo Uyeda, Mei Cong, Frank Fan, Stephen Faulkner, Bart Cornelissen
A novel pretargeted SPECT imaging strategy based on the HaloTag enzyme has been evaluated for the first time in a living system. To determine the efficacy of this approach, two clinically relevant cancer biomarkers, HER2 and TAG-72, were selected to represent models of internalizing and noninternalizing antigens, respectively. In MDA-MB-231/H2N (HER2-expressing) and LS174T (TAG-72-expressing) xenograft tumors in mice, pretargeting experiments were performed in which HaloTag-conjugated derivatives of the antibodies trastuzumab (anti-HER2) or CC49 (anti-TAG-72) were utilized as primary agents, and the small molecule HaloTag ligands (111)In-HTL-1, -2, and -3 were evaluated as secondary agents...
June 8, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28591517/an-atp-responsive-co-delivery-system-of-doxorubicin-and-mir-34a-to-synergistically-inhibit-the-cell-proliferation-and-migration
#16
Yudi Wang, Jiawen Chen, Xiao Liang, Haobo Han, Hao Wang, Yan Yang, Quanshun Li
Establishing stimuli-responsive nanosystems for the co-delivery of anticancer drug and oligonucleotide is a promising strategy in cancer treatment owing to the combination of chemotherapy and gene therapy in a synergistic manner. Herein, an ATP aptamer and its cDNA sequence were first hybridized to produce the duplex, into which chemotherapeutic agent doxorubicin (DOX) interacted through the GC-rich motif of duplex, and PEI25K was then employed as a carrier to condense the DOX-loading duplex and miR-34a to construct the ternary nanocomplex PEI/DOX-Duplex/miR-34a...
June 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28591516/impact-of-drug-rich-colloids-of-itraconazole-and-hpmcas-on-membrane-flux-in-vitro-and-oral-bioavailability-in-rats
#17
Aaron M Stewart, Michael E Grass, Timothy J Brodeur, Aaron K Goodwin, Michael M Morgen, Dwayne T Friesen, David T Vodak
Improving the oral absorption of compounds with low aqueous solubility is a common challenge that often requires an enabling technology. Frequently, oral absorption can be improved by formulating the compound as an amorphous solid dispersion (ASD). Upon dissolution, an ASD can reach a higher concentration of unbound drug than the crystalline form, and often generates a large number of sub-micron, rapidly-dissolving drug-rich colloids. These drug-rich colloids have the potential to decrease the diffusional resistance across the unstirred water layer of the intestinal tract (UWL) by acting as rapidly-diffusing shuttles for unbound drug...
June 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28548840/acceleration-of-crystal-growth-of-amorphous-griseofulvin-by-low-concentration-poly-ethylene-oxide-aspects-of-crystallization-kinetics-and-molecular-mobility
#18
Qin Shi, Chen Zhang, Yuan Su, Jie Zhang, Dongshan Zhou, Ting Cai
This study aims to investigate the crystallization behavior and molecular dynamics of amorphous griseofulvin (GSF) in the presence of low-concentration poly(ethylene oxide) (PEO). We observe that the addition of 3% w/w PEO remarkably increases the crystal growth rate of GSF by two orders of magnitude in both the supercooled liquid and glassy states. The liquid dynamics of amorphous GSF in the presence and absence of PEO are characterized by dielectric spectroscopy. With an increase of the PEO content, the α-relaxation times of the systems decrease, indicating the increase of global molecular mobility...
June 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28544850/pcpp-adjuvanted-respiratory-syncytial-virus-rsv-sf-subunit-vaccine-self-assembled-supramolecular-complexes-enable-enhanced-immunogenicity-and-protection
#19
Corinne Cayatte, Alexander Marin, Gaurav Manohar Rajani, Kirsten Schneider-Ohrum, Angie Snell Bennett, Jason D Marshall, Alexander K Andrianov
PCPP, a well-defined polyphosphazene macromolecule, has been studied as an immunoadjuvant for a soluble form of the postfusion glycoprotein of respiratory syncytial virus (RSV sF), which is an attractive vaccine candidate for inducing RSV-specific immunity in mice and humans. We demonstrate that RSV sF-PCPP formulations induce high neutralization titers to RSV comparable to alum formulations even at a low PCPP dose and protect animals against viral challenge both in the lung and in the upper respiratory tract...
June 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28544846/genomic-dna-interactions-mechanize-peptidotoxin-mediated-anticancer-nanotherapy
#20
Santosh K Misra, Aaron S Schwartz-Duval, Dipanjan Pan
Host defense peptides (HDPs) are a class of evolutionarily conserved substances of the innate immune response that have been identified as major players in the defense system in many living organisms. Some of the HDPs are also referred to as peptidotoxins, which offer immense potential for anticancer therapy. However, their therapeutic potential is yet to be fully translated mainly due to their off-target toxicity. Here we show that their nanoenabled delivery may become beneficial in controlling their delivery in intracellular space...
June 7, 2017: Molecular Pharmaceutics
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