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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/28059514/myelography-iodinated-contrast-media-ii-conformational-versatility-of-iopamidol-in-the-solid-state
#1
Barbara Bellich, Silvia Di Fonzo, Letizia Tavagnacco, Marco Paolantoni, Claudio Masciovecchio, Federica Bertolotti, Giovanna Giannini, Rita De Zorzi, Silvano Geremia, Alessandro Maiocchi, Fulvio Uggeri, Norberto Masciocchi, Attilio Cesàro
The phenomenon of polymorphism is of great relevance in pharmaceutics, since different polymorphs have different physico-chemical properties, e.g. solubility, hence, bioavailability. Coupling diffractometric and spectroscopic experiments with thermodynamic analysis and computational work opens to a methodological approach which provides information on both structure and dynamics in the solid as well as in solution. The present work reports on the conformational changes in crystalline iopamidol, which is characterized by atropisomerism, a phenomenon that influences both the solution properties and the distinct crystal phases...
January 6, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28094996/characterization-of-protein-excipient-microheterogeneity-in-biopharmaceutical-solid-state-formulations-by-confocal-fluorescence-microscopy
#2
Stijn H S Koshari, Jean L Ross, Purnendu K Nayak, Isidro E Zarraga, Karthikan Rajagopal, Norman J Wagner, Abraham M Lenhoff
Protein-stabilizer microheterogeneity is believed to influence long-term protein stability in solid-state biopharmaceutical formulations and its characterization is therefore essential for the rational design of stable formulations. However, the spatial distribution of the protein and the stabilizer in a solid-state formulation is, in general, difficult to characterize because of the lack of a functional, simple, and reliable characterization technique. We demonstrate the use of confocal fluorescence microscopy with fluorescently labeled monoclonal antibodies (mAbs) and antibody fragments (Fabs) to directly visualize three-dimensional particle morphologies and protein distributions in dried biopharmaceutical formulations, without restrictions on processing conditions or the need for extensive data analysis...
January 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28094956/radiolabeled-r954-derivatives-for-imaging-bradykinin-b1-receptor-expression-with-positron-emission-tomography
#3
Hsiou-Ting Kuo, Jinhe Pan, Joseph Lau, Chengcheng Zhang, Jutta Zeisler, Nadine Colpo, Francois Benard, Kuo-Shyan Lin
Peptide receptors have emerged as promising targets for diagnosis and therapy. The aberrant overexpression of these receptors in different cancer subtypes allows for the adoption of new treatment strategies that complement conventional chemotherapies. Bradykinin B1 receptor (B1R) is a G protein-coupled receptor that is overexpressed in many cancers, with limited expression in healthy tissues. Previously, we developed 68Ga- and 18F-labeled derivatives of B1R antagonist peptides B9858 and B9958, and successfully targeted B1R-expressing tumor xenografts in vivo...
January 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28094954/backbone-degradable-hpma-copolymer-conjugates-with-gemcitabine-and-paclitaxel-impact-of-molecular-weight-on-activity-toward-human-ovarian-carcinoma-xenografts
#4
Jiyuan Yang, Rui Zhang, Huaizhong Pan, Yuling Li, Yixin Fang, Libin Zhang, Jindrich Kopecek
Degradable diblock and multiblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer - gemcitabine (GEM) and - paclitaxel (PTX) conjugates were synthesized by RAFT copolymerization followed by click reaction for preclinical investigation. The aim was to validate the hypothesis that long-circulating conjugates are needed to generate a sustained concentration gradient between vasculature and a solid tumor, resulting in significant anticancer effect. To evaluate the impact of molecular weight of the conjugates on treatment efficacy, diblock-, tetrablock- and hexablock GEM and PTX conjugates were administered intravenously to nude mice bearing A2780 human ovarian xenografts...
January 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28094952/effect-of-an-enhanced-nose-to-brain-delivery-of-insulin-on-mild-and-progressive-memory-loss-in-the-senescence-accelerated-mouse
#5
Noriyasu Kamei, Misa Tanaka, Hayoung Choi, Nobuyuki Okada, Takamasa Ikeda, Rei Itokazu, Mariko Takeda-Morishita
Insulin is now considered to be a new drug candidate for treating dementias, such as Alzheimer's disease, whose pathologies are linked to insulin resistance in the brain. Our recent work has clarified that a noncovalent strategy involving cell-penetrating peptides (CPPs) can increase the direct transport of insulin from the nasal cavity into the brain parenchyma. The present study aimed to determine whether the brain insulin level increased by intranasal coadministration of insulin with the CPP penetratin has potential for treating dementia...
January 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28094532/preclinical-comparison-of-albumin-binding-radiofolates-impact-of-linker-entities-on-the-in-vitro-and-in-vivo-properties
#6
Klaudia Siwowska, Stephanie Haller, Francesca Bortoli, Martina Benešová, Viola Groehn, Peter Bernhardt, Roger Schibli, Cristina Müller
Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor α (FR)-positive cancer. Recently, it was shown that modification of radiofolates with an albumin-binding entity increased the tumor-to-kidney ratios of accumulated radioactivity in mice. The goal of this study was to evaluate the lead compound cm10 and compare it with new albumin-binding folate conjugates. Compound cm12 was designed with a long spacer consisting of a PEG-11 entity, and compound cm13 contained a short alkane chain between the albumin-binding moiety and folic acid...
January 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28026951/polymer-drug-nanoparticles-combine-doxorubicin-carrier-and-heparin-bioactivity-functionalities-for-primary-and-metastatic-cancer-treatment
#7
Ling Mei, Yayuan Liu, Chunyu Xia, Yubei Zhou, Zhirong Zhang, Qin He
Here, a biocompatible amphiphilic copolymer of low molecular weight heparin (LMWH) and doxorubicin (DOX) connected by an acid-sensitive hydrazone bond for enhanced tumor treatment efficacy and safety has been designed and tested. The conjugate combines DOX delivery with LMWH antimetastatic capabilities. After the nanoparticles reach the tumor site, the acidic tumor microenvironment triggers the breakage of the hydrazone bond releasing DOX from the nanoparticles, which results in an increase in the cellular uptake and enhanced in vivo antitumor efficacy...
January 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28088862/self-assembling-peptides-epitopes-as-a-novel-platform-for-anti-cancer-vaccination
#8
Mazda Rad-Malekshahi, Marieke F Fransen, Małgorzata Krawczyk, Mercedeh Mansourian, Meriem Bourajjaj, Jian Chen, Ferry Ossendorp, Wim E Hennink, Enrico Mastrobattista, Maryam Amidi
The aim of the present study was to improve the immunogenicity of peptide epitope vaccines using novel nanocarriers based on self-assembling materials. Several studies demonstrated that peptide antigens in nanoparticulate forms induce stronger immune response than their soluble forms. However, several issues such as poor loading and risk of inducing T cell anergy due to premature release of antigenic epitopes have challenged the clinical success of such systems. In the present study, we developed two vaccine delivery systems by appending a self-assembling peptide (Ac-AAVVLLLW-COOH) or a thermosensitive polymer poly(N-isopropylacrylamide (pNIPAm) to the N-terminus of different peptide antigens (OVA250-264, HPV-E743-57) to generate self-assembling peptide epitopes (SAPEs)...
January 14, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28048942/therapeutic-efficacy-of-a-family-of-phlip-mmaf-conjugates-in-cancer-cells-and-mouse-models
#9
Kelly E Burns, Harvey Hensley, Matthew K Robinson, Damien Thévenin
The targeting of therapeutics specifically to diseased tissue is crucial for the development of successful cancer treatments. The approach here is based on the pH(low) insertion peptide (pHLIP) for the delivery of a potent mitotic inhibitor monomethyl auristatin F (MMAF). We investigated six pHLIP variants conjugated to MMAF to compare their efficacy in vitro against cultured cancer cells. While all pHLIP-MMAF conjugates exhibit potent pH- and concentration-dependent killing, their cytotoxicity profiles are remarkably different...
January 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28081601/combination-therapy-of-nsclc-using-hsp90-inhibitor-and-doxorubicin-carrying-functional-nanoceria
#10
Shoukath Sulthana, Tuhina Banerjee, Jyothi Kallu, Sudershini Reddy Vuppala, Blaze Heckert, Shuguftha Naz, Tyler Shelby, Olivia Yambem, Santimukul Santra
K-RAS driven Non-Small-Cell Lung Cancer (NSCLC) represents major cause of death amongst smokers. Recently, nanotechnology has introduced novel avenues for the diagnosis and personalized treatment options for cancer. Herein, we report a novel, multifunctional nanoceria platform loaded with unique combination of two therapeutic drugs: Doxorubicin (Doxo) and Hsp90 inhibitor ganetespib (GT), for the diagnosis and effective treatment of NSCLC. We hypothesize that the use of ganetespib synergizes and accelerates the therapeutic efficacy of Doxo via ROS production, while minimizes potential cardiotoxicity of doxorubicin drug...
January 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28080053/lipid-drug-conjugate-for-enhancing-drug-delivery
#11
Danielle Irby, Chengan Du, Feng Li
Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. The conjugation of lipids to drug molecules increases lipophilicity and also changes other properties of drugs. The conjugates demonstrate several advantages including improved oral bioavailability, improved targeting to the lymphatic system, enhanced tumor targeting, and reduced toxicity. Based on the chemical nature of drugs and lipids, various conjugation strategies and chemical linkers can be utilized to synthesize LDCs...
January 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28032772/self-assembly-pegylation-retaining-activity-spra-technology-via-a-host-guest-interaction-surpassing-conventional-pegylation-methods-of-proteins
#12
Tatsunori Hirotsu, Taishi Higashi, Irhan Ibrahim Abu Hashim, Shogo Misumi, Koki Wada, Keiichi Motoyama, Hidetoshi Arima
Polyethylene glycol (PEG) modification (PEGylation) is one of the best approaches to improve the stabilities and blood half-lives of protein drugs; however, PEGylation dramatically reduces the bioactivities of protein drugs. Here, we present "self-assembly PEGylation retaining activity" (SPRA) technology via a host-guest interaction between PEGylated β-cyclodextrin (PEG-β-CyD) and adamantane-appended (Ad) proteins. PEG-β-CyD formed stable complexes with Ad-insulin and Ad-lysozyme to yield SPRA-insulin and SPRA-lysozyme, respectively...
January 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27936768/oligomerization-study-of-human-organic-anion-transporting-polypeptide-1b1
#13
Chunxu Ni, Xuan Yu, Zihui Fang, Jiujiu Huang, Mei Hong
Organic anion-transporting polypeptides play important roles in the uptake of various endogenous and exogenous compounds. It has been proposed that OATP family members, as membrane proteins, may form oligomers. However, oligomerization status of OATPs is still largely unclear. In the present study, HEK293 cells stably expressing OATP1B1 were generated to investigate the oligomerization status of the transporter. Chemical cross-linking and coimmunoprecipitation experiments revealed that OATP1B1 may form homo-oligomers, possibly through disulfide bonds...
January 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28026965/assessing-the-efficacy-of-poly-n-isopropylacrylamide-for-drug-delivery-applications-using-molecular-dynamics-simulations
#14
Soroush Moghadam, Ronald G Larson
All-atom molecular dynamic simulations (AA-MD) are performed for aqueous solutions of hydrophobic drug molecules (phenytoin) with model polymer excipients, namely, (1) N-isopropylacrylamide, (pNIPAAm), (2) pNIPAAm-co-acrylamide (Am), and (3) pNIPAAm-co-dimethylacrylamide (DMA). After validating the force field parameters using the well-known lower critical solution behavior of pNIPAAm, we simulate the polymer-drug complex in water and its behavior at temperatures below (295 K) and above the LCST (310 K). Using radial distribution functions, we find that there is an optimum comonomer molar fraction of around 20-30% DMA at which interaction with phenytoin drug molecules is strongest, consistent with recent experimental findings...
January 11, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28068767/microneedle-assisted-skin-permeation-by-non-toxic-bioengineerable-gas-vesicle-nanoparticles
#15
Abhay U Andar, Ram Karan, Wolf T Pecher, Priya DasSarma, William D Hedrich, Audra L Stinchcomb, Shiladitya DasSarma
Gas vesicle nanoparticles (GVNPs) are hollow, buoyant protein organelles produced by the extremophilic microbe Halobacterium sp. NRC-1 and are being developed as bioengineerable and biocompatible antigen and drug-delivery systems (DDS). Dynamic light scattering measurements of purified GVNP suspensions showed a mean diameter of 245 nm. In vitro diffusion studies using Yucatan miniature pig skin showed GVNP permeation to be enhanced after MN-treatment compared to untreated skin. GVNPs were found to be non-toxic to mammalian cells (human kidney and rat mycocardial myoblasts)...
January 9, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28068097/characterization-of-phase-separation-propensity-for-amorphous-spray-dried-dispersions
#16
Daniel McNamara, Shawn Yin, Duohai Pan, George Crull, Peter Timmins, Balvinder Vig
A generalized screening approach, applying isothermal calorimetry at 37°C 100%RH, to formulations of spray dried dispersions (SDDs) for two active pharmaceutical ingredients (APIs) (BMS-903452 and BMS-986034) is demonstrated. APIs 452 and 034, with similar chemotypes, were synthesized and promoted during development for oral dosing. Both APIs were formulated as SDDs for animal exposure studies using the polymer hydroxypropylmethlycellulose acetyl succinate M grade (HPMCAS M). 452 formulated at 30% (wt/wt%) was an extremely robust SDD that was able to withstand 40°C 75%RH open storage conditions for 6 months with no physical evidence of crystallization or loss of dissolution performance...
January 9, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28060514/targeted-covalent-inhibition-of-grb2-sos1-interaction-through-proximity-induced-conjugation-in-breast-cancer-cells
#17
Yongsheng Yu, Yunyu Nie, Qian Feng, Jiale Qu, Rui Wang, Liming Bian, Jiang Xia
Targeted covalent inhibitors of protein-protein interactions differ from reversible inhibitors in that the former bind and covalently bond the target protein at a specific site of the target. The site specificity is the result of the proximity of two reactive groups at the bound state, for example one mild electrophile in the inhibitor and a natural cysteine in the target close to the ligand binding site. Only a few pharmaceutically relevant proteins have this structural feature. Grb2, a key adaptor protein in maintaining the ERK activity via binding Sos1 to activated RTKs, is one: the N-terminal SH3 domain of Grb2 (Grb2N-SH3) carries a unique solvent-accessible cysteine Cys32 close to its Sos1-binding site...
January 6, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28055215/salecan-based-ph-sensitive-hydrogels-for-insulin-delivery
#18
Xiaoliang Qi, Wei Wei, Junjian Li, Gancheng Zuo, Xihao Pan, Ting Su, Jianfa Zhang, Wei Dong
Stimuli-responsive polymeric hydrogels are promising and appealing delivery vehicles for protein/peptide drugs and has made protein/peptide delivery with both dosage- and spatiotemporal-controlled manners possible. Here a series of new Salecan-based pH-sensitive hydrogels were fabricated for controlled insulin delivery via the graft copolymerization reaction between Salecan and 2-acrylamido-2-methyl-1-propanesulfonic acid. In this study, on one hand, Salecan played a key role in modifying the structure and the pore size of the developing hydrogel...
January 5, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27997198/in-vivo-drug-delivery-performance-of-lipiodol-based-emulsion-or-drug-eluting-beads-in-patients-with-hepatocellular-carcinoma
#19
Elsa Lilienberg, Ilse R Dubbelboer, Amar Karalli, Rimma Axelsson, Torkel B Brismar, Charlotte Ebeling Barbier, Agneta Norén, Frans Duraj, Mikael Hedeland, Ulf Bondesson, Erik Sjögren, Per Stål, Rickard Nyman, Hans Lennernäs
Doxorubicin (DOX) delivered in a lipiodol-based emulsion (LIPDOX) or in drug-eluting beads (DEBDOX) is used as palliative treatment in patients with intermediate-stage hepatocellular carcinoma (HCC). The primary objective of this study was to evaluate the in vivo delivery performance of DOX from LIPDOX or DEBDOX in HCC patients using the local and systemic pharmacokinetics of DOX and its main metabolite doxorubicinol (DOXol). Urinary excretion of DOX and DOXol and their short-term safety and antitumor effects were also evaluated...
January 5, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28049295/64cu-labeled-trastuzumab-fab-peg24-egf-radioimmunoconjugates-bispecific-for-her2-and-egfr-pharmacokinetics-biodistribution-and-tumor-imaging-by-pet-in-comparison-to-monospecific-agents
#20
Luke Yongkyu Kwon, Deborah A Scollard, Raymond M Reilly
: Heterodimerization of EGFR with HER2 co-expressed in breast cancer (BC) promotes tumor growth and increased EGFR expression is associated with trastuzumab resistance. Our aim was to construct 64Cu-labeled bispecific radioimmunoconjugates (bsRIC) composed of trastuzumab Fab which binds HER2 linked through a polyethylene glycol (PEG24) spacer to EGF, and compare their pharmacokinetic, biodistribution and tumor imaging characteristics by positron-emission tomography (PET). bsRICs were generated by linking malemide modified trastuzumab Fab with thiolated EGF through a thioether bond...
January 3, 2017: Molecular Pharmaceutics
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