主题： Active and Nanoparticlemediated Transport across the Blood-Brain Barrier in vitro
报告人：Hans-Joachim Galla

    Westf?lische Wilhelms-Universit?t, Institute for Biochemistry, Münster, Germany
时间：2014年11月17日上午9:00
地点：医学楼402栋一楼会议室
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附摘要：

The central nervous system (CNS) is protected by the blood– brainbarrier (BBB), which is mainly composed of capillary endothelial cellsconnected by narrow tight junctions, which prevent paracellular diffusion ofpolar molecules. In addition to its protective function, the BBB ensuressufficient nutrient supply of the brain by regulating the transport ofendogenous compounds and controlling their selective and specific uptake,efflux and metabolism. A special transport feature is the so-called multi-drugresistance (MDR). ATP depended efflux pumps (ABC-transporters) prevent thetreatment of brain diseases by active export of drugs from the brain back intothe blood stream.

This paper will introduce an in vitro porcine brain derived cell culturesystem that closely resembles the BBB in vivo. The cells express the tightjunctions thus forming a firm barrier, which could be easily quantified byimpedance spectroscopy measuring the electrical resistance. Mainly due to thepresence of the MDR more than 95% of potentially active compounds are not ableto overcome the BBB in a pharmacologically sufficient concentration.

To facilitate brain availability various delivery and targetingstrategies (1) to overcome the BBB are currently under investigation:

·        Expression and the regulation of the activity of different ABCtransporters in the brain with special interest on the ABCC3 transporter, whichhas been reconstituted in proteoliposomes and which was shown to act in acooperative manner with respect to transport and ATPase activity (2).Inhibition of the ABC transporters will enhance brain availability of drugs.

·        Use of surface modified and biologically degradable polymericnanoparticles as drug carriers. Another approach proposed by us is theinduction of a reversible disruption of the barrier by nanoparticles, which offersthe possibility to use these particles as specific opener of the BBB. Insteadof incorporating the therapeutic agents into the NP, the drugs may cross theBBB after being applied simultaneously in a Trojan Horse mechanism (3).

·        Iron oxide nanoparticles as contrast agents in MRI diagnosisfunctionalized by lactoferrin are transferred to the brain by receptor-mediatedtranscytosis with an excellent in vivo/in vitro correlation (4).

·        The brain uptake of therapeutically enzymes to cure enzyme defects inneuronal cells is possible by chemical modification (5).

[1] Cramer,S.,RempeR., and Galla HJ., Cur. Med. Chem.2013, 19, 3163-3187

   Rempe R, Cramer S, Qiao R andGalla HJ (2014)  Cell Tissue Res; 355, 717 – 726

[2]  Seelheim P, Wüllner A and Galla HJ ,Biophys.Chem 2013,171, 31-37

[3]  Rempe R.,Cramer S., Hüwel S.and Galla HJ, Biochim.Biophys.Res.Commun. 2013,406, 64-69

[4]  R.Qiao, Q.Jia, S.Hüwel, R.Xia, T.Liu, F.Gao, HJ.Galla and M. Gao; ACS Nano 2012,4,3304-10

CV Prof. Dr.Hans Joachim Galla

Male,born September 21, 1948

1969 – 1973          Studies ofchemistry, University of G?ttingen

1975                      PhD. atthe Max-Planck-Institut (MPI) for Biophysical Chemistry, University ofG?ttingen, 1976 Research Associate at the MPI, G?ttingen

1976 – 1979         Research Associate,Inst. for Biophysics, at the University of Ulm

1979                      HabilitationUniversity of Ulm

1979 – 1980          AssistantProfessor, Stanford University,

1981 – 1983         Heisenbergscholarship, Independent Group leader, University of Ulm

      1983 -1990            Professor for Biochemistry, Institute ofBiochemistry,
                                   Technical University of Darmstadt

1990 - 2016           Full Professorfor Biochemistry, Institute of Biochemistry, University of Münster

1990- 2014            Director ofthe Institute

Services and honours:

1992/1993             Dean of theFaculty

1993 – 1997          Member of theSenate of the University of Münster

Since 2003            Board member“International Graduate School in Chemistry” and chair

       2002                       Scienceaward of the University of Münster

1996 – 2002          Member of theBoard of the European Cell and Tissue Society

1976 – 2002          VicePresident of the European Cell and Tissue Society

2002 – 2006          President ofthe German branch of the European Cell and Tissue Society

2002 – 2006          Member of theBoard of the German Biophysical Society

2002 - 2006          Secretary ofthe German Biophysical Society

2007                      Eva-LuiseK?hler Award for Rare Diseases behind the Blood-Brain Barrier

Since 2008            Member ofthe Board of the German Biophysical Society

2011 – 2014          President ofthe German Biophysical Society

2013/2014             VisitingProfessor at the Institute for Chemistry, Chinese Academy of Science

                           Beijing