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Molecular Pharmaceutics

Qi Zhang, Mohammad Reza Vakili, Xing-Fang Li, Afsaneh Lavasanifar, X Chris Le
In this study, we developed a micellar platform composed of terpolymers for the encapsulation of inorganic arsenite or arsenous acid (As(III)). For this purpose, a series of terpolymers composed of poly(ethylene oxide) (PEO, block A), poly(α-carboxylate-ε-carprolactone) (PCCL, block B), and poly(ε-caprolactone) (PCL, block C) with either a blocked, i.e., BC or CB, or random, i.e., (B/C)ran block copolymer sequence in the polyester segment was synthesized. The COOH groups on block B were further modified with mercaptohexylamine for As(III) encapsulation...
November 4, 2016: Molecular Pharmaceutics
Chih-Kuang Chen, Szu-Chieh Huang
Chitosan/polyvinyl alcohol (CS/PVA) hybrid nanofibers via electrospinning have been extensively used as wound dressing materials. However, there are still several drawbacks associated with their processing procedures and material properties, including the necessity of using acid solutions as spinning solvents, the need of employing highly toxic cross-linkers, and the lack of stimuli-responsive functions. In this context, water soluble N-maleoyl functional chitosan (MCS) was successfully synthesized and well characterized...
November 3, 2016: Molecular Pharmaceutics
Tae Hwan Kim, Soyoung Shin, Jürgen B Bulitta, Yu Seok Youn, Sun Dong Yoo, Beom Soo Shin
Establishing a level A in vitro-in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on population pharmacokinetic (POP-PK) modeling that incorporated physiologically relevant absorption kinetics. To prepare three extended release (ER) tablets of loxoprofen, three types of hydroxypropyl methylcellulose (HPMC 100, 4000, and 15000 cps) were used as drug release modifiers, while lactose and magnesium stearate were used as the diluent and lubricant, respectively...
November 3, 2016: Molecular Pharmaceutics
F Broccatelli, L Salphati, E Plise, J Cheong, A Gobbi, M-L Lee, I Aliagas
Intestinal absorption in human is routinely predicted in drug discovery using in vitro assays such as permeability in the MDCK cell line. In silico models trained on these data are used in drug discovery efforts to prioritize novel chemical targets for synthesis, however their proprietary nature and the limited validation available, which is usually restricted to predicting in vitro permeability, is a barrier to wide-spread adoption. Due to the categorical nature of the in vitro permeability assay, intrinsic assay variability, and the challenges often encountered when translating in vitro data to an in vivo drug property, validation based solely on in vitro data might not be a good characterization of the usefulness of the in silico tool...
November 2, 2016: Molecular Pharmaceutics
Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Marco Bisoffi, Judith C Hugh, Hasan Uludag
Cancer cells are known to be heterogeneous and plastic, which imparts innate and acquired abilities to resist molecular targeting by short interfering RNA (siRNA). Not all cancer cells in a population would show a similar responsiveness to targeting of genes critical for their survival and, even the responders could quickly transform and switch to alternative mechanism(s) for their survival. This study was designed to look at this phenomenon by analyzing the effect of siRNA silencing of selected protein mRNAs involved in cell survival and proliferation on other protein mRNAs that could contribute to cell survival...
November 1, 2016: Molecular Pharmaceutics
Krishna Kattel, Goutam Mondal, Feng Lin, Virender Kumar, Ram I Mahato
Therapeutic efficacy of gemcitabine (GEM) is severely limited due to its rapid metabolism by enzymatic deamination in vivo. We recently determined its therapeutic efficacy before (F-GEM) and after conjugation to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (mPEG-b-PCC-g-GEM-g-DC, abbreviated as P-GEM) in subcutaneous and orthotopic pancreatic tumor bearing mice. In this study, pharmacokinetic (PK) parameters and biodistribution profiles of F-GEM and P-GEM were determined after intravenous injection into orthotopic pancreatic tumor bearing NSG mice...
October 31, 2016: Molecular Pharmaceutics
Yanhua Liu, Chengming Zhou, Wenping Wang, Jianhong Yang, Hao Wang, Wei Hong, Yu Huang
A novel CD44 receptor targeting and endosome pH-sensitive dual functional hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar system was designed for intracellular paclitaxel (PTX) delivery. The HA-DOCA-His micelles exhibited desirable endosome pH (5.0-6.0)-induced aggregation and deformation behavior verified by size distribution, critical micellar concentration, and zeta potential changes. The HA-DOCA-His micelles presented excellent encapsulation efficiency and loading capacity of 90.0% and 18...
October 31, 2016: Molecular Pharmaceutics
Di Li, Weiguo Xu, Pengqiang Li, Jianxun Ding, Zhiliang Cheng, Li Chen, Lesan Yan, Xuesi Chen
Self-targetability is an emerging targeted strategy for polymer nanocarriers with facile preparation and high targeting effi-ciency. An acid-sensitive dextran-doxorubicin prodrug (Dex-g-DOX) has been synthesized and used as a self-targeted drug delivery system for the treatment of orthotopic hepatoma. The polysaccharide prodrug exhibits ultra-selective accumulation in cancerous liver tissue, acid-sensitive DOX release within cells, and high antitumor efficacy in vitro and in vivo. Therefore, Dex-g-DOX demonstrates great potential for chemotherapy of orthotopic hepatoma...
October 26, 2016: Molecular Pharmaceutics
Saket Kumar Singh, Bibhas Kumar Bhunia, Nandana Bhardwaj, Sween Gilotra, Biman B Mandal
Tunable repeated drug administration is often inevitable in number of pathological cases. Reloadable 3D matrices for sustained drug delivery are predicted as a prospective avenue to realize this objective. This study was directed towards sonication-induced fabrication of novel reloadable Bombyx mori silk fibroin (SF) (4, 6 and 8 wt%) hydrogel, injected within 3D porous (8 wt%) scaffolds. The focus was to develop a dual-barrier reloadable depot system for sustained molecular cargo-release. Both the varying SF concentration (4, 6 and 8 wt%) and the sonication time (30, 45 and 60 s) dictated the extent of cross-linking, β-sheet content and porosity (1-10 µm) influencing the release behavior of model molecules...
October 26, 2016: Molecular Pharmaceutics
Zheyu Shen, Aiguo Wu, Xiaoyuan Chen
Magnetic iron oxide nanoparticles (MIONs) have attracted enormous attention due to their wide applications, including magnetic separation, magnetic hyperthermia and as contrast agents for magnetic resonance imaging (MRI). This review article introduces the methods of synthesizing MIONs, and their application as MRI contrast agents. Currently, many methods have been reported for the synthesis of MIONs. Herein, we only focus on the liquid-based synthesis methods including aqueous phase methods and organic phase methods...
October 24, 2016: Molecular Pharmaceutics
Xiao-Bin Fang, Ying-Qi Xu, Hon-Fai Chan, Chun-Ming Wang, Qing Zheng, Fei Xiao, Mei-Wan Chen
Hepatocellular carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer death worldwide. Most current therapeutic agents lack the tumor-targeting efficiency and result in a nonselective biodistribution in the body. In our previous study, we identified a peptide Ala-Pro-Asp-Thr-Lys-Thr-Gln (APDTKTQ) that can selectively bind to the receptor of advanced glycation end-products (RAGE), an immunoglobulin superfamily cell surface molecule overexpressed during HCC malignant progression. Here, we report the design of a mixed micelles system modified with this peptide to target HCC cells...
October 21, 2016: Molecular Pharmaceutics
Naveen Kumar Thakral, Robert J Behme, Aktham Aburub, Jeffrey A Peterson, Timothy A Woods, Benjamin A Diseroad, Raj Suryanarayanan, Gregory A Stephenson
Disproportionation propensity of salts (HCl, HBr, hemi-napadisylate) and adipic acid co-crystal of corticotropin releasing hormone receptor-1 antagonist, was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and co-crystal was generated based on model free kinetics. This activation energy of disproportionation provided qualitative information about the solid state salt stability. To ensure the stability throughout the shelf life, "prototype" formulations of salts and co-crystal in tablet form, were stored at 40 °C and several water vapor pressures...
October 21, 2016: Molecular Pharmaceutics
Chunfeng Lu, Wenxuan Xu, Feng Zhang, Jiangjuan Shao, Shizhong Zheng
It has emerged that hepatocyte necroptosis plays a critical role in chronic alcoholic liver disease (ALD). Our previous study has identified that the beneficial therapeutic effect of curcumin on alcohol-caused liver injury might be attributed to activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), whereas the role of curcumin in regulating necroptosis and the underlying mechanism remain to be determined. We firstly found that chronic alcohol consumption triggered obvious hepatocyte necroptosis, leading to increased expression of receptor-interacting protein 1, receptor-interacting protein 3, high-mobility group box 1, and phosphorylated mixed lineage kinase domain-like in murine livers...
October 20, 2016: Molecular Pharmaceutics
Haisheng He, Jian Zhang, Yunchang Xie, Yi Lu, Jianping Qi, Ejaj Ahmad, Xiaochun Dong, Weili Zhao, Wei Wu
One of the biggest challenges in bioimaging of nanoparticles is how to identify integral particles from bulk signals of probes. Signals of free probes are always mistakenly counted into total signals of particles. In this study, in vivo fate of intravenous polymeric micelles (PMs, mPEG2.5k-PDLLA2.5k) was explored using a highly sensitive near-infrared environment-responsive fluorescent probe. This probe is able to emit fluorescence when embedded in nanocarriers but quench spontaneously and absolutely upon release into water, based on the aggregation-caused quenching effect, which means that the interference generated by free probes can be completely diminished...
October 19, 2016: Molecular Pharmaceutics
R Onnainty, E M Schenfeld, J P Petiti, M R Longhi, A Torres, M A Quevedo, G E Granero
Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):ß-cyclodextrin (ßCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs)[CS/HCT:ßCD NPs]. It was found, for the first time, that exposure of the intestinal mucosa to free HCT resulted in an increased and abnormal intestinal permeability associated with several injuries to the intestinal epithelium. Nevertheless, the HCT delivery system obtained ameliorated the damage of the intestinal epithelium induced by HCT...
October 18, 2016: Molecular Pharmaceutics
Yuki Daimon, Noriyasu Kamei, Kohsaku Kawakami, Mariko Takeda-Morishita, Hironori Izawa, Yuki Takechi-Haraya, Hiroyuki Saito, Hideki Sakai, Masahiko Abe, Katsuhiko Ariga
The effect of carrier morphology on the intestinal absorption of insulin was investigated using a morphology-tunable polymeric carrier, β-cyclodextrin-grafted chitosan (BCC). The insulin-BCC complexes were prepared either in acetate and citrate buffer solutions, followed by dilution with phosphate buffer for the administration. The complex had a molecular network structure in the acetate buffer, whereas nanoparticles formed in the citrate buffer. The network structure in the acetate buffer was maintained even after dilution with a phosphate buffer, but the nanoparticles in the citrate buffer caused aggregation after dilution...
October 17, 2016: Molecular Pharmaceutics
Ghislain Djiokeng Paka, Charles Ramassamy
One major challenge in the field of nanotherapeutics is to increase the selective delivery of cargo to targeted cells. Using Poly Lactic-co-Glycolic Acid (PLGA), we recently highlighted the importance of polymer composition in the biological fate of the nanodrug delivery systems. However the route of internalisation of polymeric nanoparticles (NPs) is another key component to consider in the elaboration of modern and targeted devices. For that purpose, herein, we effectively synthesized and characterised glutathione- functionalized PLGA-nanoparticles (GSH-NPs) loaded with curcumin (GSH-NPs-Cur), using thiol-maleimide click reaction and determined their physicochemical properties...
October 15, 2016: Molecular Pharmaceutics
Yanping Yang, Xuedan Wang, Hui Yang, Hualong Fu, Jinming Zhang, Xiaojun Zhang, Jiapei Dai, Zhiyong Zhang, Chunping Lin, Yuzhi Guo, Mengchao Cui
This study describes an effective strategy to improve pharmacokinetics of Aβ imaging agents, offering a novel class of (R)- and (S)-18F-labeled 2-arylbenzoheterocyclic derivatives which bear an additional chiral hydroxyl group on the side chain. These ligands displayed binding abilities toward Aβ aggregates with Ki values varying from 3.2 to 195.6 nM. Chirality-related discrepancy was observed in biodistribution and (S)-2-phenylbenzoxazole enantiomers exhibited vastly improved brain clearance with washout ratios higher than 20...
October 15, 2016: Molecular Pharmaceutics
Yanping Li, Rui Li, Qinhui Liu, Wenyao Li, Ting Zhang, Min Zou, Hong Li, Tong Wu, Shihai Cheng, Zhiguang Su, Zhirong Zhang, Jinhan He
Tumor cells can acquire multidrug resistance (MDR) as a result of drug efflux mediated by P-glycoprotein (P-gp). Here we report a targeted delivery system to carry pirarubicin (THP) to MDR breast cancer both in vitro and in vivo. PEG-derivatized vitamin E (PAMV6) amphiphiles loaded with THP were self-assembled in a single step. The PAMV6 micelles showed unimodal size distribution and high drug loading efficiency. Cytotoxicity of PAMV6/THP was higher than that of free THP on MCF-7/ADR cells but comparable to that of THP on MCF-7 cells...
October 15, 2016: Molecular Pharmaceutics
Bhagyesh R Sarode, Karen Kover, Pei Y Tong, Chaoying Zhang, Simon H Friedman
In this work we demonstrate that blood glucose can be controlled remotely through light stimulated release of insulin from an injected cutaneous depot. Human insulin was tethered to an insoluble but injectable polymer via a linker, which was based on the light cleavable di-methoxy nitrophenyl ethyl (DMNPE) group. This material was injected into the skin of streptozotocin-treated diabetic rats. We observed insulin being released into the bloodstream after a 2 min trans-cutaneous irradiation of this site by a compact LED light source...
October 15, 2016: Molecular Pharmaceutics
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