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Exploring the utility of the Chasing Principle:influence of drug-free SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040 in aqueous suspension

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Acta Pharmaceutica Sinica B 2019年第1期9卷 194-201页

作者： Scheyla Daniela Siqueira j?rgensen Thomas Rades Huiling Mu Kirsten Graeser anette Müllertz Department of Pharmacy Faculty of Health and Medical Sciences University of Copenhagen Roche Pharma Research and Development Therapeutic Modalities Roche Innovation Center Basel

This study assessed the influence of the composition of drug-free SNEDDS co-dosed with aqueous suspensions of carvedilol(CAR), cinnarizine(CIN) or R3040 on drug solubilization in a twocompartment in vitro lipolysis model. Correlation of drug log P or solubility in SNEDDS with drug solubilization during in vitro lipolysis in the presence of drug-free SNEDDS was assessed. SNEDDS with varying ratios of soybean oil:Maisine 35-1(1:1, w/w) and Kolliphor RH40, with ethanol at 10%(w/w) were used. SNEDDS were named F65, F55 and F20(numbers refer to the percentage of lipids) and aqueous suspensions without drug-free SNEDDS(F0) were also analyzed. While the ranking order of drug solubilization was F65? F55? F204F0 for CAR; F65? F554F204F0 for CIN and F65? F55? F204F0 for R3040-with higher CAR solubilization than for R3040 and CIN-the ranking of S_(eq)of CAR, CIN and R3040 in SNEDDS was F65 o F55o F20, F65? F554F20 and F654F554F20, respectively. Therefore, the composition of SNEDDS influenced the solubilization of CIN, but not CAR and R3040. Furthermore, high S_(eq) in SNEDDS did not reflect high drug solubilization. As CAR(log P 3.8) showed higher solubilization than CIN(log P 5.8) and R3040(log P 10.4), a correlation between drug log P and drug solubilization was observed.

关键词： Self-nanoemulsiying drug delivery system(SNEDDS) Chasing principle Two-compartment in vitro lipolysis Rat gastrointestinal conditions Drug solubilization

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MCC1019,a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel,potent anticancer candidate

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Acta Pharmaceutica Sinica B 2019年第5期9卷 1021-1034页

作者： Sara Abdelfatah Angela Berg Qi Huang Li jun Yang Sami Hamdoun anette Klinger Henry j.Greten Edmond Fleischer Thorsten Berg Vincent K.W.Wong Thomas Efferth Department of Pharmaceutical Biology Institute of Pharmacy and BiochemistryJohannes Gutenberg UniversityMainz55128Germany Leipzig University Institute of Organic ChemistryLeipzig04103Germany State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyMacaoChina MicroCombiChem GmbH Wiesbaden65203Germany Abel Salazar Institute of Biomedical Sciences University of PortoPorto4099-003Portugal

Polo-like kinase(PLK1) has been identified as a potential target for cancer *** a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain(PBD), which has a key regulatory function for kinase activity and substrate recognition. We report on 3-bromomethylbenzofuran-2-carboxylic acid ethyl ester(designated: MCC1019) as selective PLK1 inhibitor targeting PLK1 PBD. Cytotoxicity and fluorescence polarization-based screening were applied to a library of 1162 drug-like compounds to identify potential inhibitors of PLK1 PBD. The activity of compound MC1019 against the PLK1 PBD was confirmed using fluorescence polarization and microscale *** compound exerted specificity towards PLK1 over PLK2 and PLK3. MCC1019 showed cytotoxic activity in a panel of different cancer cell lines. Mechanistic investigations in A549 lung adenocarcinoma cells revealed that MCC1019 induced cell growth inhibition through inactivation of AKT signaling pathway, it also induced prolonged mitotic arrest—a phenomenon known as mitotic catastrophe, which is followed by immediate cell death via apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth in vivo in a murine lung cancer model without affecting body weight or vital organ size, and reduced the growth of metastatic lesions in the lung. We propose MCC1019 as promising anti-cancer drug candidate.

关键词： Polo-like kinase PLK1 Polo box domain Mono-targeted therapy Cell cycle Necroptosis Spindle damage

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From Droplets and Particles to Hierarchical Spatial Organization： Nanotechnology Challenges for Microfluidics

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journal of Physical Science and Application 2011年第3期1卷 125-134页

作者： j. Michael Kohler P. Mike Gvnther anette Funfak jialan Cao Andrea Knauer Shuning Li Steffen Schneider G. Alexander Gross Techn. Univ. llmenau Institute of Micro- and Nanotechnologies/Institute for Physics Dept. Phys. Chem. and MicroreactionTechnology llmenau Germany

The compartimentation of fluids in the microliter, nanoliter and picoliter range leads recently to many applications of microfluidics in material development, diagnostics and biological screenings. Droplet-based microfluidics allows the improvement of nanoparticle homogeneity and the tuning of particle properties. It supports combinatorial synthesis of inorganic as well as organic substances and can be applied for the cultivation and screening of bacteria, eucaryotic cells and fish embryos. The well-ordered handling and the addressing of microfluid segments improves the information transfer between chemical, biological and electronic systems. Despite this remarkable technical progress, there is a particular importance of microfluidics for future nanotechnological solutions. The hierarchical spatial organization of liquids, particles and gels in microfluidics represents a fundamental biomimetic principle which overcomes the limits of planar technology and opens the gate for realizing complex structured threedimensional nanoarchitectures. Recent applications of microstructured fluids in chemistry and biology and concepts for future developments will be discussed.

关键词： Nanotechnology microfluidics nanoparticles segmented flow concentration spaces screening nested phases hierarchical organization droplet-based systems.

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Intravenous immune globulin suppresses angiogenesis in mice and humans

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Signal Transduction and Targeted Therapy 2016年第1期1卷 141-148页

作者： Reo Yasuma Valeria Cicatiello Takeshi Mizutani Laura Tudisco Younghee Kim Valeria Tarallo Sasha Bogdanovich Yoshio Hirano Nagaraj Kerur Shengjian Li Tetsuhiro Yasuma Benjamin j Fowler Charles B Wright Ivana Apicella Adelaide Greco Arturo Brunetti Balamurali K Ambati Sevim Barbasso Helmers Ingrid E Lundberg Ondrej Viklicky j.anette hw leusen j Sjef Verbeek Bradley D Gelfand Ana Bastos-Carvalho Sandro De Falco jayakrishna Ambati Department of Ophthalmology and Visual Sciences University of KentuckyLexingtonKYUSA Department of Ophthalmology Nagoya University Graduate School of MedicineNagoyaJapan Angiogenesis Lab Institute of Genetics and Biophysics—CNRNaplesItaly Bio-Ker MultiMedica GroupNaplesItaly Department of Physiology University of KentuckyLexingtonKYUSA Department of Advanced Biomedical Sciences University of Naples‘Federico II’NaplesItaly CEINGE—Biotecnologie Avanzate s.c.ar.l.NaplesItaly Department of Ophthalmology and Visual Sciences Moran Eye CenterUniversity of Utah School of MedicineSalt Lake CityUTUSA Department of Ophthalmology Veterans Affairs Salt Lake City Healthcare SystemSalt Lake CityUTUSA Rheumatology Unit Department of MedicineKarolinska InstitutetKarolinska University HospitalStockholmSweden Department of Nephrology Institute for Clinical and Experimental MedicinePrague 4Czech Republic Immunotherapy Laboratory Laboratory for Translational ImmunologyUniversity Medical Center UtrechtUtrechtThe Netherlands Department of Human Genetics Leiden University Medical CenterLeidenThe Netherlands Department of Biomedical Engineering University of KentuckyLexingtonKYUSA Department of Microbiology Immunologyand Molecular GeneticsUniversity of KentuckyLexingtonKYUSA IRCCS MultiMedica MilanoItaly

Human intravenous immune globulin(IVIg),a purified IgG fraction composed of~60%IgG1 and obtained from the pooled plasma of thousands of donors,is clinically used for a wide range of *** biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG(IgG)Fc ***,we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI,a high-affinity receptor for *** we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases,namely,neovascular age-related macular degeneration,corneal neovascularization,colorectal cancer,fibrosarcoma and peripheral arterial ischemic *** was mediated by the Fc region of IVIg,required FcγRI and had similar potency in transgenic mice expressing human Fcγ***,IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel *** data place IVIg,an agent approved by the US Food and Drug Administration,as a novel angioinhibitory drug in doses that are currently administered in the clinical *** addition,they raise the possibility of an unintended effect of IVIg on blood vessels.

关键词： doses inhibited degeneration

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Human IgG1 antibodies suppress angiogenesis in a target-independent manner

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Signal Transduction and Targeted Therapy 2016年第1期1卷 158-171页

作者： Sasha Bogdanovich Younghee Kim Takeshi Mizutani Reo Yasuma Laura Tudisco Valeria Cicatiello Ana Bastos-Carvalho Nagaraj Kerur Yoshio Hirano judit Z Baffi Valeria Tarallo Shengjian Li Tetsuhiro Yasuma Parthasarathy Arpitha Benjamin j Fowler Charles B Wright Ivana Apicella Adelaide Greco Arturo Brunetti Menotti Ruvo Annamaria Sandomenico Miho Nozaki Ryo Ijima Hiroki Kaneko Yuichiro Ogura Hiroko Terasaki Balamurali K Ambati j.anette hw leusen Wallace Y Langdon Michael R Clark Kathryn L Armour Pierre Bruhns j Sjef Verbeek Bradley D Gelfand Sandro De Falco jayakrishna Ambati Department of Ophthalmology and Visual Sciences University of KentuckyLexingtonKYUSA Department of Ophthalmology and Visual Science Nagoya City University Graduate School of Medical SciencesNagoyaJapan Department of Ophthalmology Nagoya University Graduate School of MedicineNagoyaJapan Angiogenesis Lab Institute of Genetics and Biophysics—CNRNaplesItaly Bio-Ker MultiMedica GroupNaplesItaly Department of Advanced Biomedical Sciences University of Naples‘Federico II’NaplesItaly CEINGE—Biotecnologie Avanzate s.c.a.r.l.NaplesItaly Istituto di Biostrutture e Bioimmagini CNRNaplesItaly Department of Ophthalmology and Visual Sciences Moran Eye CenterUniversity of Utah School of MedicineSalt Lake CityUTUSA Department of Ophthalmology Veterans Affairs Salt Lake City Healthcare SystemSalt Lake CityUTUSA Immunotherapy Laboratory Laboratory for Translational ImmunologyUniversity Medical Center UtrechtUtrechtThe Netherlands School of Pathology and Laboratory Medicine University of Western AustraliaCrawleyWAAustralia Division of Immunology Department of PathologyUniversity of CambridgeCambridgeUK Department of Immunology Unit of Antibodies in Therapy and PathologyInstitut PasteurParisFrance Institut National de la Santéet de la Recherche Médicale(INSERM)U1222 ParisFrance Department of Human Genetics Leiden University Medical CenterLeidenThe Netherlands Department of Biomedical Engineering University of KentuckyLexingtonKYUSA Department of Microbiology Immunologyand Molecular GeneticsUniversity of KentuckyLexingtonKYUSA IRCCS MultiMedica MilanoItaly Department of Physiology University of KentuckyLexingtonKYUSA.

Aberrant angiogenesis is implicated in diseases affecting nearly 10%of the world’s *** most widely used antiangiogenic drug is bevacizumab,a humanized IgG1 monoclonal antibody that targets human *** bevacizumab does not recognize mouse Vegfa,it inhibits angiogenesis in *** we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI(CD64)and c-Cbl,impairing macrophage *** approved humanized or human IgG1 antibodies without mouse targets(adalimumab,alemtuzumab,ofatumumab,omalizumab,palivizumab and tocilizumab),mouse IgG2a,and overexpression of human IgG1-Fc or mouse IgG2a-Fc,also inhibited angiogenesis in wild-type and FcγR humanized *** anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown,Fc cleavage,IgG-Fc inhibition,disruption of Fc-FcγR interaction,or elimination of FcRγ-initated ***,bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA ***,mice deficient in FcγRI exhibited increased developmental and pathological *** findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

关键词： CD64 angiogenesis antibodies

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远程耦合世界的可持续性框架

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生态学报 2016年第23期36卷 7870-7885页

作者：刘建国 Vanessa Hull Mateus Batistella Ruth DeFries Thomas Dietz 付峰 Thomas W.Hertel R.Cesar Izaurralde Eric F.Lambin 李舒心 Luiz A.Martinelli William j.McConnell Emilio F.Moran Rosamond Naylor 欧阳志云 KarenR.Polenske anette Reenberg Gilberto de Miranda Rocha Cynthia S.Simmons Peter H.Verburg Peter M.Vitousek 张福锁朱春全 Michigan State University USA EMBRAPA Satellite Monitoring CampinasSPBrazil Columbia University USA Massachusetts Institute of Technology USA Purdue University USA University of Maryland USA Stanford University USA CENA University of Sao Paulo(USP) PiracicabaSao PaoloBrazil Chinese Academy of Sciences BeijingChina University of Copenhagen CopenhagenDenmark Federal University of Para Brazil Institute for Environmental Studies VU University AmsterdamNetherlands China Agricultural University BeijingChina International Union for Conservation of Nature China

远距离之间的相互作用及其影响日益广泛。这种远程相互作用往往会对可持续发展产生深远的影响并会造成意想不到的结果。很多可持续性研究都是针对某个特定地点进行的,很少注重多个地点之间远程相互作用对可持续性所产生的影响。虽然有... 详细信息

远距离之间的相互作用及其影响日益广泛。这种远程相互作用往往会对可持续发展产生深远的影响并会造成意想不到的结果。很多可持续性研究都是针对某个特定地点进行的,很少注重多个地点之间远程相互作用对可持续性所产生的影响。虽然有些研究涉及到远程因素,但通常都把它们看作外在变量,而未把它们看作反馈。为了更好地理解和综合各种远程相互作用,本文提出了一种基于远程耦合的综合框架,它是一个远距离社会经济和环境相互作用的总体概念。人类与自然耦合系统是研究在特定地点发生的相互作用,远程耦合概念是对人类与自然耦合系统研究的自然延伸。远程耦合框架包括五个相关的组成部分,即:人类与自然耦合系统、流、代理、原因、和影响。本文通过农产品贸易和物种入侵两个远程相互作用的例子来解释远程耦合框架,重点阐述远程耦合框架的影响,并讨论促进远程耦合研究发展的研究条件和方法。这个框架有助于分析系统内各组成部分以及它们之间的相互关系,找出研究差距,探索其中的隐含成本以及尚未开发的优势,提供引入反馈及多系统(发送、接收和外溢系统)之间权衡和协同的有效手段,从本地到全球各个层面加深对远程相互作用的认识,并提高社会经济和环境可http://***持续发展政策的有效性。

关键词：代理原因人类与环境耦合系统人类与自然耦合系统社会与生态耦合系统扩散远程相互作用影响反馈流全球化投资知识传播迁移社会经济与环境相互作用物种入侵可持续性技术转让远程连接远程耦合贸易跨国土地交易水转移

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