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Molecular Pharmaceutics

Zhengyuan Zhou, Darryl Lynn McDougald, Nick Devoogdt, Michael R Zalutsky, Ganesan Vaidyanathan
ImmunoPET agents are being investigated to assess the status of epidermal growth factor receptor 2 (HER2) in breast cancer patients with the goal of selecting those likely to benefit from HER2-targeted therapies and monitoring their progress after these treatments. We have been exploring the use of single domain antibody fragments (sdAbs) labeled with 18 F using residualizing prosthetic agents for this purpose. In this study, we have labeled two sdAbs that bind to different domains on the HER2 receptor - 2Rs15d and 5F7 - using 2,3,5,6-tetrafluorophenyl 6-[18F]fluoronicotinate ([18 F]TFPFN) and evaluated their HER2 targeting properties in vitro and in vivo...
November 14, 2018: Molecular Pharmaceutics
Alexandre Melkoumov, Isabelle St-Jean, Xavier Banquy, Gregoire Leclair, Jeanne Leblond-Chain
Drugs and proteins with poor intestinal permeability have a limited oral bioavailability. To remediate this problem, a receptor-mediated endocytosis and transcytosis approach was explored. Indeed, the non-toxic β subunit of cholera toxin (CTB) can cross the intestinal barrier by binding to receptor GM1. In this study, we explored the use of GM1-binding peptides and CTB as potential covalent carriers of poorly permeable molecules. GM1-binding peptides (G23, P3) and CTB were conjugated to poorly permeable fluorescent probes such as FITC and albumin-FITC using triethylene glycol spacers and click chemistry...
November 13, 2018: Molecular Pharmaceutics
Zili Suo, Xinnuo Xiong, Qiaomei Sun, Ludan Zhao, Peixiao Tang, Quan Hou, Yongkui Zhang, Di Wu, Hui Li
Dabrafenib is a novel targeted anti-melanoma drug. The present work explored the binding mechanism of dabrafenib-human serum albumin (HSA) and the effect on the esterase-like activity and antioxidant activity of HSA by using 19F NMR, spectroscopy methods, and molecular dynamics simulation. The results of 19F NMR, fluorescence, and time-resolved fluorescence spectroscopy revealed that dabrafenib spontaneously binds to the subdomain IIIA of the HSA by hydrophobic action and forms a static complex. The binding affects the esterase-like activity of HSA but not its antioxidant activity...
November 13, 2018: Molecular Pharmaceutics
Alexander Zaremba, Frieder Helm, Gert Fricker
ABC-transporters act as efflux pumps, thereby influencing pharmacokinetics and efficacy of many drugs. Zinc (Zn) is an essential trace element contributing to cellular growth and differ-entiation. It is increasingly recognized as intracellular messenger. The present study aims at investigating the impact of Zn2+ on function and regulation of ABC transporters at the blood-brain barrier (BBB). ABC transporter function was first studied in isolated rat brain capillar-ies. Zn2+ rapidly stimulated the activity of the multidrug resistance-related protein 2 (Mrp2), p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp)...
November 13, 2018: Molecular Pharmaceutics
Hywel D Williams, Leigh Ford, Sifei Han, Kristian J Tangso, Shea Lim, David M Shackleford, David T Vodak, Hassan Benameur, Colin W Pouton, Peter J Scammells, Christopher J H Porter
The absolute bioavailability of many small molecule kinase inhibitors (smKIs) is low. The reasons for low bioavailability are multifaceted and include constraints due to first pass metabolism and poor absorption. For smKIs where absorption limits oral bioavailability, low aqueous solubility and high lipophilicity, often in combination with high-dose requirements have been implicated in low and variable absorption, food-effects, and absorption-related drug-drug interactions. The current study has evaluated whether preparation of smKIs as lipophilic salts/ionic liquids in combination with coadministration with lipid-based formulations is able to enhance absorption for examples of this compound class...
November 13, 2018: Molecular Pharmaceutics
Paulo Paixão, Marival Bermejo, Bart Hens, Yasuhiro Tsume, Joseph Dickens, Kerby Shedden, Niloufar Salehi, Mark J Koenigsknecht, Jason R Baker, William L Hasler, Robert Lionberger, Jianghong Fan, Jeffrey Wysocki, Bo Wen, Allen Lee, Ann Frances, Gregory E Amidon, Alex Yu, Gail Benninghoff, Raimar Löbenberg, Arjang Talattof, Duxin Sun, Gordon L Amidon
Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions...
November 12, 2018: Molecular Pharmaceutics
Toshiki Kurosawa, Yuma Tega, Kei Higuchi, Tomoko Yamaguchi, Takashi Nakakura, Tatsuki Mochizuki, Hiroyuki Kusuhara, Kenji Kawabata, Yoshiharu Deguchi
Brain microvascular endothelial cells derived from human induced pluripotent stem cells (hiPS-BMECs) have been proposed as a new blood-brain barrier model, but their transport function has not been fully clarified. Therefore, in this study, we investigated the gene expression and function of transporters in hiPS-BMECs by means of quantitative reverse transcription-PCR, in vitro transcellular transport studies, and uptake experiments. mRNAs encoding ABC and SLC transporters, such as BCRP, MCT1, CAT1, and GLAST, were highly expressed in hiPS-BMECs...
November 12, 2018: Molecular Pharmaceutics
Lefkothea C Papadopoulou, Alexandra Ingendoh-Tsakmakidis, Christina N Mpoutoureli, Lamprini D Tzikalou, Efthymia D Spyridou, George I Gavriilidis, Georgios C Kaiafas, Agoritsa T Ntaska, Efthymia Vlachaki, George Panayotou, Martina Samiotaki, Asterios S Tsiftsoglou
Protein replacement therapy (PRT) has been applied to treat severe monogenetic/metabolic disorders characterized by a protein deficiency. In disorders where an intracellular protein is missing, PRT is not easily feasible due to the inability of proteins to cross the cell membrane. Instead, gene therapy has been applied, although still with limited success. β-Thalassemias are severe congenital hemoglobinopathies, characterized by deficiency or reduced production of the adult β-globin chain. The resulting imbalance of α-/β-globin chains of adult hemoglobin (α2 β2 ) leads to precipitation of unpaired α-globin chains and, eventually, to defective erythropoiesis...
November 12, 2018: Molecular Pharmaceutics
Hiroyuki Watanabe, Masashi Yoshimura, Kohei Sano, Yoichi Shimizu, Sho Kaide, Yuji Nakamoto, Kaori Togashi, Masahiro Ono, Hideo Saji
Deposition of islet amyloid consisting of amylin constitutes one of pathological hallmarks of type 2 diabetes mellitus (T2DM), and it may be involved in the development and progression of T2DM. However, the details about the relationship between the deposition of islet amyloid and the pathology of T2DM remain unclear, since no useful imaging tracer enabling the visualization of pancreatic amylin is available. In the present study, we synthesized and evaluated six novel 18 F-labeled phenoxymethylpyridine (PMP) derivatives as amylin imaging probes...
November 8, 2018: Molecular Pharmaceutics
Yang Hu, Pieter J Gaillard, Jaap Rip, Elizabeth C M de Lange, Margareta Hammarlund-Udenaes
Despite the promising features of liposomes as brain drug delivery vehicles, it remains uncertain how they influence the brain uptake in vivo. In order to gain a better fundamental understanding of the interaction between liposomes and the blood-brain barrier (BBB), it is indispensable to test if liposomes affect drugs with different BBB transport properties (active influx or efflux) differently. The aim of this study was to quantitatively evaluate how PEGylated (PEG) liposomes influence brain delivery of diphenhydramine (DPH), a drug with active influx at the BBB, in rats...
November 8, 2018: Molecular Pharmaceutics
Thota Ganesh, Avijit Banik, Ray Dingledine, Wenyi Wang, Radhika Amaradhi
The prostaglandin E2 receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life and low aqueous solubility, which renders them sub-optimal for testing in animal models of disease...
November 6, 2018: Molecular Pharmaceutics
Claudia A J van Winkel, Alberto Moreno, David T Curiel
The adenovirus (Ad) is widely used as a vaccine because of its ability to induce a cellular and humoral immune response. In addition, human clinical trials have validated the safety and efficacy of Ad as a vaccine vector. The traditional approach for employing the adenovirus as vaccine is to configure the antigen genes into the expression cassette of the Ad genome. An alternative method for inducing an immune response is the "capsid-incorporation" strategy. This strategy is based upon the incorporation of proteins or peptides into the capsid proteins...
November 6, 2018: Molecular Pharmaceutics
Lu Shan, Neil Mody, Pietro Sormanni, Kim Rosenthal, Melissa Damschroder, Reza Esfandiary
Monoclonal antibodies (mAbs) are complex molecular structures. They are often prone to development challenges particularly at high concentrations due to undesired solution properties such as reversible self-association, high viscosity, and liquid-liquid phase separation. In addition to formulation optimization, applying protein engineering can provide an alternative mitigation strategy. Protein engineering during the discovery phase can provide great benefits to optimize molecular properties, resulting in improved developability profiles...
November 5, 2018: Molecular Pharmaceutics
Jingtao Zhang, Xinpei Mao, Wei Xu
Peptide aggregation, such as the formation of fibrils, could pose a significant challenge for the stability of parenteral peptide drugs. To ensure a robust peptide formulation, a thorough understanding of aggregation kinetics and the development of appropriate accelerated testing conditions are necessary. The present research investigated factors that impact the fibrillation kinetics of a helical 29mer pharmaceutical peptide (peptide A) and attempts to correlate results of accelerated kinetic studies with real time kinetics...
November 5, 2018: Molecular Pharmaceutics
Mengbi Yang, Qian Zhang, Qianwen Wang, Kasper K Sørensen, Josephine T Boesen, Sum Yi Ma, Knud J Jensen, Kin Ming Kwan, Jacky Chi Ki Ngo, Ho Yin Edwin Chan, Zhong Zuo
Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutic that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities respectively, have been previously demonstrated by us with combinational therapeutic effects on Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals...
November 3, 2018: Molecular Pharmaceutics
Yihui Deng, Mingqi Liu, Xiang Luo, Qiujun Qiu, Le Kang, Tang Li, Junqiang Ding, Yan Xiong, Zitong Zhao, Chuqing Chang, Jinlei Zan, Xinrong Liu, Yanzhi Song
With increasing application of PEGylated products, drawbacks are beginning to emerge, such as the 'PEG dilemma'. Other promising materials may need to be found in the current situation. Endogenous polysialic acid (PSA), which is highly expressed on mammalian, bacterial and malignant surface, may be a promising material in oncology. In this study, a dual-responsive amphiphilic PSA cholesterol derivative (PSA-CS-CH) was synthesized to explore the opportunity of PSA in targeted drug delivery systems. PSA-CS-CH, F127 mixed micelles (PF-M) and pure F127 micelles (F-M) were prepared for comparative anti-tumor experiments...
November 3, 2018: Molecular Pharmaceutics
Elaine F Enright, Kalaimathi Govindarajan, Rebecca Darrer, John MacSharry, Susan A Joyce, Cormac G M Gahan
Once regarded as obscure, the cohabitation of man and microbe has gained increasing recognition as a determinant of the health status of the host. Pharmacokinetic research at the host-microbe interface has been primarily directed towards effects on metabolism, with comparatively fewer investigations considering effects on the absorption process. We previously demonstrated that the transcriptional expression of genes encoding intestinal transporters involved in lipid translocation are altered in germ-free and conventionalized mice possessing distinct bile acid signatures...
November 2, 2018: Molecular Pharmaceutics
Yuemin Wang, Xiaomei Chen, Dahua He, Yi Zhou, Linghao Qin
Anticancer drugs cannot be located in the tumor efficiently when intravenously administered because of their weak tissue specificity and often present the problems of low therapeutic activity and severe adverse effects. To conquer these challenges, a targeting nanomedicine system based on human body cells or cell derivates have drawn more attention from scientists in recent decades. In this work, we used doxorubicin (DOX) as a model drug and a nanoerythrocyte modified with folic acid (FA) and polyethylene glycol (PEG) as a carrier to develop a novel tumor targeting drug delivery system (FA/PEG-DOX-Nano-RBCs) to enhance antitumor efficacy and reduce drug-related toxicity...
November 1, 2018: Molecular Pharmaceutics
Julia Mantaj, Tamara Abu-Shams, Zachary Enlo-Scott, Magda Swedrowska, Driton Vllasaliu
Full understanding of the barrier property of mucosal tissues is imperative for development of successful mucosal drug delivery strategies, particularly for biologics and nanomedicines. The contribution of the mucosal basement membrane (BM) to this barrier is currently not fully appreciated. This work examined the role of the BM as a barrier to intestinal absorption of model macromolecules (5 kDa and 10 kDa dextrans) and 100 nm polystyrene nanoparticles. Dextrans and nanoparticles were applied either directly to BM-coated inserts or to an intestinal model, namely differentiated intestinal epithelial monolayers (Caco-2) cultured on BM-modified inserts...
October 31, 2018: Molecular Pharmaceutics
Anima M Schaefer, Thomas Bock, Henriette E Meyer Zu Schwabedissen
The organic anion transporting polypeptide (OATP) 2B1 is ubiquitously expressed and known to facilitate cellular entry. It is widely accepted that transport proteins play a pivotal role in pharmacokinetics. Consequently, testing for interaction with drug transporters became an important part in the assessment of new molecular entities in order to predict and prevent drug-drug interactions. Recently competitive counterflow (CCF) an indirect method allowing the identification of substrates was successfully applied to the organic cation transporter 2...
October 31, 2018: Molecular Pharmaceutics
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