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Molecular Pharmaceutics

Federico Baruffaldi, April Huseby Kelcher, Megan Laudenbach, Valeria Gradinati, Ajinkya Limkar, Michaela Roslawski, Angela Birnbaum, Andrew Lees, Carla Hassler, Scott P Runyon, Marco Pravetoni
Vaccines may offer a new treatment strategy for opioid use disorders and opioid-related overdoses. To speed translation, this study evaluates opioid conjugate vaccines containing components suitable for pharmaceutical manufacturing and compares analytical assays for conjugate characterization. Three oxycodone-based haptens (OXY) containing either PEGylated or tetraglycine [(Gly)4] linkers were conjugated to keyhole limpet hemocyanin (KLH) carrier protein via carbodiimide (EDAC) or maleimide chemistry. The EDAC-conjugated OXY(Gly)4-KLH was most effective in reducing oxycodone distribution to the brain in mice...
September 21, 2018: Molecular Pharmaceutics
Na An, Yun Nan Hou, Qiao Xia Zhang, Ting Li, Qiong Li Zhang, Cheng Fang, Huan Chen, Hon Cheung Lee, Yong Juan Zhao, Xin Du
Chimeric antigen receptor T cells (CAR-Ts) are a promising strategy for the treatment of many cancers, including multiple myeloma (MM), a hematological malignancy characterized by the high expression of CD38. To broaden the applications of using CD38 as a therapeutic target for the disease, we developed a new nanobody against CD38 and constructed a CD38-CAR that was composed of this nanobody as the targeting domain, and 4-1BB and CD3ζ as the costimulatory and activating domains, in a lentiviral vector. CD3+ T cells from healthy individuals were transduced with the CD38-CAR at an efficiency higher than 60%, as determined by CD38-CAR expression using flow cytometry...
September 21, 2018: Molecular Pharmaceutics
Feng Li, Huixia Zhang, Miao He, Jinhui Liao, Nianhang Chen, Yan Li, Simon Zhou, Maria Palmisano, Alex Yu, Manjunath P Pai, Hebao Yuan, Duxin Sun
Previous studies have shown that different paclitaxel formulations produce distinct anticancer efficacy and safety profiles in animals and humans. This study aimed to investigate the distinct pharmacokinetics and tissue distribution of various nanoformulations of paclitaxel, which may translate into potential differences in safety and efficacy. Four nanoparticle formulations ( nab-paclitaxel, mouse albumin nab-paclitaxel [m -nab-paclitaxel], micellar paclitaxel, and polymeric nanoparticle paclitaxel) as well as solvent-based paclitaxel were intravenously administered to mice...
September 21, 2018: Molecular Pharmaceutics
Kseniia Porshneva, Diana Papiernik, Mateusz Psurski, Marcin Nowak, Rafał Matkowski, Marcin Ekiert, Magdalena Milczarek, Joanna Banach, Joanna Jarosz, Joanna Wietrzyk
Vascular endothelial dysfunction and platelet activation play a key role in tumor metastasis, and therefore both of these processes are considered important therapeutic targets in cancer. The aim of our studies was to analyze anti-metastatic activity of combination therapy using nitric oxide donor DETA/NO and antiplatelet drug clopidogrel. Nitric oxide acts as a vasoprotective mediator, while clopidogrel inhibits ADP-mediated platelet aggregation. 4T1-luc2-tdTomato cell line transplanted intravenously (i.v...
September 20, 2018: Molecular Pharmaceutics
Manuel E Minas da Piedade, Ricardo G Simoes, Carlos E S Bernardes, Abhinav Joseph, M Fátima M da Piedade, Werner Kraus, Franziska Emmerling, Herminio P Diogo
Simvastatin is one of the most widely used active pharmaceutical ingredients for the treatment of hyperlipidemias. Because the compound is employed as a solid in drug formulations, particular attention should be given to the characterization of different polymorphs, their stability domains and the nature of the phase transitions that relate them. In this work the phase transitions delimiting the stability domains of three previously reported simvastatin forms were investigated from structural, energetics, and dynamical points of view, based on single crystal X-ray diffraction (SCXRD), hot stage microscopy (HSM) and differential scanning calorimetry (DSC) experiments (conventional scans and heat capacity measurements), complemented with molecular dynamics (MD) simulations...
September 19, 2018: Molecular Pharmaceutics
Yi-Ni Cao, Asiya Baiyisaiti, Chui-Wei Wong, Shan-Hui Hsu, Rong Qi
Polyurethane (PU) nanoparticles are potential drug carriers. We aimed to study the in vitro and in vivo efficacy of biodegradable PU nanoparticles loaded with fenofibrate (FNB-PU) on nonalcoholic fatty liver disease (NAFLD). FNB-PU was prepared by a green process, and its preventive effects on NAFLD were investigated on HepG2 cells and mice. FNB-PU showed sustained in vitro FNB release profile. Compared to FNB crude drug, FNB-PU significantly decreased triglyceride content in HepG2 cells incubated with oleic acid and in livers of mice with NAFLD induced by a methionine choline deficient diet, and increased plasma FNB concentration of the mice...
September 19, 2018: Molecular Pharmaceutics
Daniil Polykovskiy, Alexander Zhebrak, Dmitry Vetrov, Yan Ivanenkov, Vladimir Aladinskiy, Polina Mamoshina, Marine Bozdaganyan, Alexander Aliper, Alex Zhavoronkov, Artur Kadurin
Modern computational approaches and machine learning techniques accelerate the invention of new drugs. Generative models can discover novel molecular structures within hours, while conventional drug discovery pipelines require months of work. In this article, we propose a new generative architecture, entangled conditional adversarial autoencoder, that generates molecular structures based on various properties, such as activity against a specific protein, solubility, or ease of synthesis. We apply the proposed model to generate a novel inhibitor of Janus kinase 3, implicated in rheumatoid arthritis, psoriasis, and vitiligo...
September 19, 2018: Molecular Pharmaceutics
William M Pardridge, Ruben J Boado, Daniel J Patrick, Eric Ka-Wai Hui, Jeff Zhiqiang Lu
A monoclonal antibody (MAb) against the blood-brain barrier (BBB) transferrin receptor (TfR) is a potential agent for delivery of biologic drugs to brain across the BBB. However, to date, no TfRMAb has been tested with chronic dosing in a primate model. A humanized TfRMAb against the human (h) TfR1, which cross reacts with the primate TfR, was genetically engineered with high affinity (ED50=0.18 ± 0.04 nM) for the human TfR type 1 (TfR1). For acute dosing, the hTfRMAb was tritiated and injected intravenously (IV) in the Rhesus monkey, which confirmed rapid delivery of the humanized hTfRMAb into both brain parenchyma, via transport across the BBB, and into cerebrospinal fluid (CSF), via transport across choroid plexus...
September 18, 2018: Molecular Pharmaceutics
Maryam A Shetab Boushehri, Alf Lamprecht
Toll-like Receptor 4 (TLR4) agonists have had a long journey in the field of cancer immunotherapy. Nevertheless, despite the remarkable number of the TLR4 ligands that have gone through various pre-clinical and clinical stages, only two (Bacillus Calmette-Guérin (BCG) and monophosphoryl lipid A (MPLA)) have hitherto obtained the FDA approval for clinical application in cancer treatment. This paper provides a comprehensive review of the TLR4 agonists' journey as cancer active immunotherapeutics. Following a brief discussion of the rational behind the use of TLR ligands in cancer immunotherapy, we will initially focus on the forerunner of the TLR4 agonists, bacterial lipopolysaccharide (LPS)...
September 18, 2018: Molecular Pharmaceutics
Ivana Roscoe, Michelle Parker, Daoyuan Dong, Xun Li, Zhiyu Li
Human serum albumin (HSA) fusion protein is a viable and effective approach to target and inhibit essential intracellular pathways. It has previously been shown that an HSA fusion protein containing a p53-reactivating peptide (rHSA-p53i) retains the binding activity to MDM2 and MDMX, resulting in p53 transcription-dependent apoptosis. Here, we demonstrate that rHSA-p53i is able to bind and neutralize anti-apoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1. This interaction displaces pro-apoptotic Bak and subsequently leads to intrinsic apoptosis via mimicking a p53 transcription-independent pathway...
September 18, 2018: Molecular Pharmaceutics
Dylan M Glatt, Denis R Beckford Vera, Shamit S Prabhu, J Christopher Luft, S Rahima Benhabbour, Matthew C Parrott
The safety and efficacy of anticancer antibody-drug conjugates (ADC) depend on the selection of tumor-targeting monoclonal antibody (mAb), linker, and drug, as well as their specific chemical arrangement and linkage chemistry. In this study, we used a bifunctional linker to conjugate docetaxel (DX) to cetuximab (CET) or panitumumab (PAN). The resulting double-drug ADCs were investigated for their in vitro EGFR-specific cytotoxicity and in vivo anticancer activity. Reaction conditions, such as reducing agent, time, temperature, and alkylation buffer, were optimized to yield potent and stable ADCs with consistent batch-to-batch DARs...
September 18, 2018: Molecular Pharmaceutics
Martha Ariza-Sáenz, Marta Espina, Ana Calpena, Maria J Gómara, Ignacio Pérez-Pomeda, Isabel Haro, María Luisa García
New therapeutic alternatives in the fight against the spread of HIV-1 are based on peptides designed to inhibit the early steps of HIV-1 fusion in target cells. However, drawbacks such as: bioavailability, short half-life, rapid clearance and poor ability to cross the physiological barriers make such peptides unattractive for the pharmaceutical industry. Here in this study we developed, optimized and characterized polymeric nanoparticles (NPs) coated with glycol chitosan (GC) to incorporate and release an HIV-1 fusion inhibitor peptide (E1), inside the vaginal mucosa...
September 18, 2018: Molecular Pharmaceutics
Lu-Ning Li, Lei Wang, Yanna Cheng, Zhan-Qi Cao, Xin-Ke Zhang, Xiuli Guo
Sambutoxin, a representative derivative of 4-hydroxy-2-pyridone, was isolated from Hericium alpestre for the first time in this study. The possible correlation between the sambutoxin-induced suppression of tumor growth and its influence on cell cycle arrest and apoptosis was investigated. The effects of sambutoxin on reactive oxygen species (ROS) production, DNA damage, mitochondrial transmembrane potential, cell apoptosis and the expression of related proteins were evaluated. An in vitro cell viability study demonstrated that sambutoxin could inhibit the proliferation of various cancer cells...
September 17, 2018: Molecular Pharmaceutics
Hairui Zhang, Tania F Bahamondez-Canas, Yajie Zhang, Jasmim Leal, Hugh D C Smyth
Chitosan has been widely employed to deliver nucleic acids such as siRNA and plasmids. However, chitosan-mediated delivery of gene-editing system has not been reported yet. In this study, poly(ethylene glycol) monomethyl ether (mPEG) was conjugated to chitosan with different molecular weights (low molecular weight and medium molecular weight chitosan) achieving a high degree of substitution as identified by fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1 H NMR) spectra...
September 17, 2018: Molecular Pharmaceutics
Eugene C Chen, Fabio Broccatelli, Emile Plise, Buyun Chen, Liling Liu, Jonathan Cheong, Shu Zhang, Jamie Jorski, Katherine Gaffney, Kayla K Umemoto, Laurent Salphati
Permeability assays are commonly conducted with Madin-Darby canine kidney (MDCK) cells to predict the intestinal absorption of small molecule drug candidates. In addition, MDCK cells transfected to overexpress efflux transporters are often used to identify substrates. However, MDCK cells exhibit endogenous efflux activity for a significant proportion of experimental compounds, potentially leading to the underestimation of permeability and confounded findings in transport studies. The goal of this study was to evaluate canine Mdr1 knockout MDCK (gMDCKI) cells in permeability screening and human MDR1 substrate determination in a drug discovery setting...
September 17, 2018: Molecular Pharmaceutics
Yichao Chen, Jingjing Sun, Yixian Huang, Binfeng Lu, Song Li
It is highly demanded and still a big challenge to develop an effective formulation for immunochemotherapy against advanced tumors. We have previously reported a PEG-NLG-based immunostimulatory nanocarrier (PEG2k-Fmoc-NLG919) for codelivery of an IDO1 inhibitor (NLG919) and a chemotherapeutic agent (paclitaxel, PTX). Although antitumor immune responses were enhanced with PTX-loaded nanocarrier, the accumulation of myeloid-derived suppressor cells (MDSCs) was also significantly increased, which may limit the overall efficacy of therapy...
September 17, 2018: Molecular Pharmaceutics
L U Xue, Nita J Maihle, Xiaolin Yu, Shou-Ching Tang, Hong Yan Liu
HER2 overexpression is identified on 20-30% breast cancer and other cancers at different levels. Although HER2 targeted monoclonal antibody combined with chemical drugs has shown improved outcomes in HER2 expressing patients, drug resistance and toxicity have limited their efficacy. To overcome drug resistance, co-targeting of multiple HER receptors was proved to be effective. EGFR /HER2 dimerization can active PI3K/AKT pathway, and resistance to HER2-targeted drugs is associated with upregulation of EGFR. Here, we developed a novel HER2/EGFR targeted nucleic acid therapeutic to address current drug limits...
September 17, 2018: Molecular Pharmaceutics
Gaoxing Su, Huaqiao Jiang, Bohui Xu, Yanyan Yu, Xueqin Chen
Protein corona can alter the physiochemical properties of targeting nanoparticles (NPs), as well as their physiological responses and targeting functionality. Herein, we synthesized 20 types of NPs with diverse surface chemistry in order to study the impacts of protein corona on targeting functionality of cyclic RGD peptides, and their relationships to the polyethylene glycol (PEG) length and grafting density of targeting ligands. After protein adsorption, cyclic RGD on the surface of NP was still able to bind its receptors with increased targeted cell uptake, even at relatively low density...
September 17, 2018: Molecular Pharmaceutics
Gianpaolo Dagrada, Katia Rupel, Serena Zacchigna, Elena Tamborini, Silvana Pilotti, Adalberto Cavalleri, Loryn E Fechner, Erik Laurini, David K Smith, Silvia Brich, Sabrina Pricl
Solitary fibrous tumors (SFTs) are rare soft tissue sarcomas that rely on several epithelial-mesenchymal transition (EMT) protein regulators for invasion/metastatic progression. Curcumin (CUR) has several pharmacological activities, including anticancer activity and the ability to suppress the EMT process. However, poor absorption, rapid metabolism, and side effects at high doses limit the clinical applications of CUR. Here we present the results obtained by treating SFT cells with free CUR and three different CUR-loaded nanomicelles (NMs), each of which has its surface decorated with different ligands...
September 17, 2018: Molecular Pharmaceutics
Paroma Chakravarty, Antonio DiPasquale, Andreas Stumpf, Joseph W Lubach, Karthik Nagapudi
GENE-A, a Nav1.7 inhibitor compound with analgesic activity was developed as a crystalline anhydrate, for which two polymorphic forms, I and II, were discovered. The two forms were found to possess very similar free energies as determined experimentally with Form II being thermodynamically stable above 292K (19o C) based on solubility measurements. A detailed solid-state characterization was conducted to determine the relative stability of these solid forms, and both thermodynamic and kinetic pathways (slurry bridging and crystallization) were evaluated...
September 14, 2018: Molecular Pharmaceutics
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