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Molecular Pharmaceutics

Yogesh Patil, Panayiotis Bilalis, Georgios Polymeropoulos, Sarah R Almahdali, Nikos Hadjichristidis, Valentin O Rodionov
A well-defined amphiphilic miktoarm polymer incorporating poly(vinylidene fluoride) (PVDF), polystyrene (PS), and poly(ethylene glycol) (PEG) blocks was synthesized via a combination of atom-transfer radical polymerization (ATRP), iodine transfer radical polymerization (ITP), and copper-catalyzed azide-alkyne cycloaddition (CuAAC). Morphology and self-assembly of this star polymer were examined in organic solvents and in water. The aggregates formed in water were found to possess unusual frustrated topology due to immiscibility of PS and PVDF...
March 15, 2018: Molecular Pharmaceutics
Petr Chytil, Milada Sirova, Júlia Kudláčová, Blanka Rihova, Karel Ulbrich, Tomáš Etrych
Herein, the biodegradable micelle-forming amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer conjugates with the anti-cancer drug doxorubicin (Dox) designed for enhanced tumor accumulation were investigated, and the influence of their stability in the blood stream on biodistribution, namely, tumor uptake, and in vivo antitumor efficacy were evaluated in detail. Dox was attached to the polymer carrier by a hydrazone bond enabling pH-controlled drug release. While the polymer-drug conjugates were stable in a buffer at pH 7...
March 15, 2018: Molecular Pharmaceutics
Dvora Izgelov, Irina Cherniakov, Gefen Aldouby Bier, Abraham J Domb, Amnon Hoffman
In recent years, Phase II metabolism, as a first pass metabolism process occurring to the parent drug, is gaining more and more attention. This is due to its acknowledged significance in drug development as well as drug-drug interactions. However, the predominant role of Phase I metabolism has always overshadowed Phase II metabolism, resulting in insufficient data regarding its mechanisms. In this paper, we investigate the effect of an advanced lipid based drug delivery system on Phase II metabolism at the intestinal level of the enterocytes monolayer...
March 14, 2018: Molecular Pharmaceutics
Lei Kang, Dawei Jiang, Emily B Ehlerding, Todd E Barnhart, Dalong Ni, Jonathan W Engle, Rongfu Wang, Peng Huang, Xiaojie Xu, Weibo Cai
CD30 has been considered a unique diagnostic and therapeutic target for CD30-positive lymphomas and some lung diseases. Additionally, CD30 has shown high expression in clinical lung cancer samples. In this study,89 Zr-radiolabeled Brentuximab vedotin (BV) was developed for in vivo tracking of BV and imaging CD30 expression in lung cancer models via conjugation with desferrioxamine (Df). CD30 expression in three lung cancer cell lines (H460, H358, and A549) was quantified by Western blot. Flow cytometry and saturation binding assays were used to evaluate the binding capabilities of the tracer in vitro...
March 14, 2018: Molecular Pharmaceutics
Junhua Mai, Xin Li, Guodong Zhang, Yi Huang, Rong Xu, Qi Shen, Ganesh Lakshmana Rao Lokesh, Varatharasa Thiviyanathan, Lingxiao Chen, Haoran Liu, Youli Zu, Xiaojing Ma, David E Volk, David G Gorenstein, Mauro Ferrari, Haifa Shen
Selective drug accumulation in the malignant tissue is a prerequisite for effective cancer treatment. However, most drug molecules and their formulated particles are blocked en route to the destiny tissue due to the existence of multiple biological and physical barriers including the tumor microvessel endothelium. Since the endothelial cells on the surface of the microvessel wall can be modulated by inflammatory cytokines and chemokines secreted by the tumor or stromal cells, an effective drug delivery approach is to enhance interaction between the drug particles and the unique spectrum of surface proteins on the tumor endothelium...
March 14, 2018: Molecular Pharmaceutics
Brian Luk, Yao Jiang, Jonathan Copp, Che-Ming J Hu, Nishta Krishnan, Weiwei Gao, Shulin Li, Ronnie H Fang, Liangfang Zhang
Within the body, cellular recognition is mediated in large part by receptor-ligand interactions that result from the surface marker expression of the participant cells. In the case of immune cells, these interactions can be highly specific, enabling them to carry out their protective functions in fighting off infection and malignancy. In this work, we demonstrate the biomimetic targeting of antigen-specific immune cell populations by using nanoparticles functionalized with natural membrane derived from cells expressing the cognate antigen...
March 13, 2018: Molecular Pharmaceutics
Gudrun A Fridgeirsdottir, Rob Harris, Ian Dryden, Peter M Fischer, Clive J Roberts
Solid dispersions can be a successful way to enhance the bioavailability of poorly soluble drugs. Here 60 solid dispersion formulations were produced using ten chemically diverse, neutral, poorly soluble drugs, three commonly used polymers, and two manufacturing techniques, spray drying and melt extrusion. Each formulation underwent a six-month stability study at accelerated conditions, 40 °C and 75% relative humidity (RH). Significant differences in times to crystallisation (onset of crystallisation) were observed between both the different polymers and the two processing methods...
March 13, 2018: Molecular Pharmaceutics
Shihong Shao, Yun Zhu, Tingting Meng, Yupeng Liu, Yun Hong, Ming Yuan, Hong Yuan, Fuqiang Hu
Liver metastasis is a leading death cause in colorectal cancer. The pathological differences between orthotopic tumors and metastatic lesions increased the therapeutic difficulty of metastasis. Herein, the α5β1 integrin receptor expression on metastatic cells was firstly measured, the result showed that metastatic cells expressed higher α5β1 integrin compared with original cells from orthotopic tumors. Afterwards, RPM peptide modified chitosan-stearic (RPM-CSOSA) was designed based on α5β1 integrin expression...
March 13, 2018: Molecular Pharmaceutics
Michelle H Fung, Kārlis Bērziņš, Raj Suryanarayanan
In an earlier investigation, coamorphous systems of ketoconazole (KTZ) prepared with each oxalic (OXA), tartaric (TAR), citric (CIT) and succinic (SUC) acid, revealed drug-acid ionic and/or hydrogen bonding interactions in the solid-state (Fung et al, Mol Pharmaceutics, 2018, 15(x), xxxx-yyyy). We showed that the drug-acid interactions in KTZ-TAR were the strongest, followed by KTZ-OXA, KTZ-CIT and KTZ-SUC. In this study, we investigated the crystallization propensity and dissolution behavior of the KTZ-acid coamorphous systems...
March 12, 2018: Molecular Pharmaceutics
Jahidur Rashid, Kamrun Nahar, Snehal Raut, Ali Keshavarz, Fakhrul Ahsan
We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long acting nitric oxide donorboth loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC)in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified- and CAR-modified-liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia induced PAH rats...
March 12, 2018: Molecular Pharmaceutics
Lili Zhao, Xin Ni, Linlin Zhao, Yao Zhang, Dan Jin, Wei Yin, Dandan Wang, Wei Zhang
Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. MicroRNAs have been increasingly implicated in NSCLC and may serve as novel therapeutic targets to combat cancer. Here we investigated the functional implication of miR-188 in NSCLC. We first analyzed miR-188 expression in both NSCLC clinical samples and cancer cell lines. Next we investigated its role in A549 and H2126 cells with cell proliferation, migration and apoptosis assays. To extend the in vitro study, we employed both xenograft model and LSL-K-ras G12D lung cancer model to examine the role of miR-188 in tumorigenesis...
March 12, 2018: Molecular Pharmaceutics
Jingjie Tan, Chan Li, Qian Wang, Shuyi Li, Shizhu Chen, Jinchao Zhang, Paul C Wang, Lei Ren, Xing-Jie Liang
Flurbiprofen, a hydrophobic COX inhibitor, was coordinated axially with oxoplatin to form a new conjugate cis, cis, trans-[Pt(IV)(NH3)2Cl2(flurbiprofen)2]. The successful synthsis of this new conjugate was confirmed by 1H, 13C and 195Pt NMR. The potential of this conjugate being reduced to cisplatin and subsequently exerting its DNA cross-linking ability was verified using cyclic voltammetry (CV), HPLC and mass spectrum (MS). This conjugate showed markedly higher cytotoxicity on many cancer cell lines than cisplatin, flurbiprofen and physical mixture (mol ratio, cisplatin: flurbiprofen=1:2) of them...
March 9, 2018: Molecular Pharmaceutics
Kanchan Chauhan, Anjani K Tiwari, Nidhi Chadha, Ankur Kaul, Ajai Kumar Singh, Anupama Datta
Homodimeric chalcone based11 C-PET radiotracer,11 C-(Chal)2 DEA-Me was synthesized and binding affinity towards beta amyloid (Aβ) was evaluated. The computational studies revealed multiple binding of the tracer at the recognition sites of Aβ fibrils. The bivalent ligand,11 C-(Chal)2 DEA-Me displayed higher binding affinity compared to the corresponding monomer,11 C-Chal-Me and classical Aβ agents. The radiolabeling yield with carbon-11 was 40-55% (decay corrected) with specific activity of 65‒90 GBq/μmol...
March 9, 2018: Molecular Pharmaceutics
Dawen Kou, Chen Zhang, Hiuwing Yiu, Tania Ng, Joseph W Lubach, Matthew Janson, Chen Mao, Matthew Durk, Leslie Chinn, Helen Winter, Larry Wigman, Peter Yehl
In this study, a multi-pronged approach of in vitro experiments, in silico simulations, and in vivo studies was developed to evaluate the dissolution, supersaturation, precipitation, and absorption of three formulations of Compound-A, a BCS Class 2 weak base with pH-dependent solubility. In in vitro 2-stage dissolution experiments, the solutions were highly supersaturated with no precipitation at the low dose but increasing precipitation at higher doses. No difference in precipitation was observed between the capsules and tablets...
March 9, 2018: Molecular Pharmaceutics
Wei Zhang, Abbe Haser, Hao Helen Hou, Karthik Nagapudi
The accuracy of amorphous solubility advantage calculation was evaluated by experimental solubility measurement. Ten structurally diverse compounds were studied to test the generality of the theoretical calculation. Three reported methods of calculating Gibbs free energy difference between amorphous and crystalline solids were evaluated. Experimental solubility advantage was measured by direct dissolution of amorphous solid in buffer. When necessary, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was pre-dissolved in buffer to inhibit desupersaturation...
March 9, 2018: Molecular Pharmaceutics
Tania F Bahamondez-Canas, Hairui Zhang, Frederic Tewes, Jasmim Leal, Hugh D C Smyth
Pseudomonas aeruginosa is the predominant pathogen in the persistent lung infections of cystic fibrosis (CF) patients among other diseases. One of the mechanisms of resistance of P. aeruginosa infections is the formation and presence of biofilms. Previously, we demonstrated that PEGylated-tobramycin (Tob-PEG) had superior antimicrobial activity against P. aeruginosa biofilms compared to tobramycin (Tob). The goal of this study was to optimize the method of PEGylation of Tob and assess its activity in an in vitro CF-like mucus barrier biofilm model...
March 7, 2018: Molecular Pharmaceutics
Laura I Mosquera-Giraldo, Na Li, Venecia R Wilson, Brittany L B Nichols, Kevin J Edgar, Lynne S Taylor
During dissolution of amorphous solid dispersions (ASDs), various phase transformation can occur, which will ultimately impact the degree of supersaturation. This study employed dissolution and diffusion measurements to compare the performance of various ASD formulations based on the maximum amount of free drug in solution that was able to permeate through a cellulose based membrane. Telaprevir (TPV) was used as the model drug compound, and ASDs were prepared with different drug loadings and using four different polymers...
March 7, 2018: Molecular Pharmaceutics
Qianqian Zhao, Nikhila Miriyala, Yan Su, Weijie Chen, Xuejiao Gao, Ling Shao, Yitao Wang, Ru Yan, Haifeng Li, Xiao-Jun Yao, Dong-Sheng Cao, Defang Ouyang
Cyclodextrin (CD) complexation is widely used for the solubilization of poorly soluble drugs in the pharmaceutical industry. Current research was to develop a highly-soluble lutein-cyclodextrin multiple-component delivery system (lutein-CD-MCDS) by combined modeling and experimental approaches. Both phase solubility diagram and molecular dynamics (MD) simulation results revealed that the interactions between lutein and CDs were very weak, which confirmed the insignificant solubility improvement of lutein-CD binary system...
March 5, 2018: Molecular Pharmaceutics
Linlin Miao, Jia Su, Xuezhi Zhuo, Lifeng Luo, Yihan Kong, Jingxin Gou, Tian Yin, Yu Zhang, Haibing He, Xing Tang
The clinical application of disulfiram (DSF) in cancer treatments is hindered by its rapid degradation in the blood circulation. In this study, methoxy poly(ethyleneglycol)-b-poly(lactide-co-glycolide)/poly(ε-caprolactone) (mPEG5k-b-PLGA2k/PCL3.4k) micelles were developed for encapsulation of DSF -by using the emulsification-solvent diffusion method. Medium chain triglyceride (MCT) was incorporated into the mixed polymeric micelles to improve drug loading by reducing the core crystallinity. Differential scanning calorimetry (DSC) results implied that DSF is likely present in an amorphous form within the micelles, and is well dispersed...
March 5, 2018: Molecular Pharmaceutics
Arjang Talattof, Gordon L Amidon
Fasted-state gastrointestinal (GI) fluid transit is typically represented as a first-order, deterministic process (averaged and viewed as a continuous approximation). It is, however, most likely a discrete process involving fluid packets interrupted by variable time periods of little to no fluid emptying. In this report we present a physiologically based pulsed-packet gastric fluid emptying model and evaluate it with respect to recent gastrointestinal fluid volume emptying results, published gastric emptying of various dosage forms, and gastric fluid emptying as a function of GI motility...
March 5, 2018: Molecular Pharmaceutics
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