Publikationsserver der Universitätsbibliothek Marburg
Titel:Untersuchungen zum Einsatz nanopartikulärer Trägersysteme zur Transfektion von Immun- und Alveolarzellen mit therapeutischen DNAzymen
Autor:Paul, Christoph
Weitere Beteiligte: Garn, Holger (Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0416
DOI: https://doi.org/10.17192/z2012.0416
URN: urn:nbn:de:hebis:04-z2012-04169
DDC: Medizin
Titel (trans.):Investigations on the use of nanoparticular vector systems for the transfection of immun and alveolar cells with therapeutic DNAzymes
Publikationsdatum:2012-07-11
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Asthma, Tran sfektion, Zellkultur, Immunsystem, Transfection, Lung, Lunge, DNAzym, DNAzyme, Transfektion, Asthma, Allergisches Asthma, Lunge

Zusammenfassung:
Asthma bronchiale gehört weltweit zu den häufigsten chronischen Lungenerkrankungen. Eine wichtige Rolle in der Pathogenese des allergischen Asthmas spielen T-Helferzellen (TH2) für deren Differenzierung und Aktivierung der Transkriptionsfaktor GATA-3 essentiell ist. Durch lokale Applikation eines GATA-3 mRNA spaltenden DNAzyms - ein DNA-Oligonukleotid mit katalytischer Aktivität - konnte im Tiermodell ein Asthma Phänotyp bereits erfolgreich therapiert werden. Die Aufnahme der DNAzym-Moleküle in ihre Zielzellen ist jedoch auf Grund ihrer Ladung und Größe herausfordernd, so dass in der vorliegenden Arbeit der Frage nachgegangen wurde, ob natürliches Surfactant oder künstliche Vektoren die Aufnahme und somit die Wirksamkeit von GATA-3 spezifischen DNAzymen verbessern können. Zur Untersuchung in vitro setzten wir dafür ein fluoreszenzmarkiertes DNAzym ein, dessen Aufnahme in verschiedene Zelllinien unter Einfluss von Surfactant sowie Polyethylenimin (PEI) und Polyethylenimin-Polyethylenglycol (PEI-PEG) Polymeren durchflusszytometrisch analysiert wurde. Zwei verschiedene Surfactant-Präparationen (Alveofact®, Curosurf®) führten dabei in verschiedenen Versuchsaufbauten zu keiner Veränderung der Aufnahme - unsere Ergebnisse liefern somit keinen Hinweis auf die in der Literatur vertretene Hypothese, Surfactant verbessere die Aufnahme von DNA in vitro. Die eingesetzten PEI und PEI-PEG Moleküle hingegen führten zu einer effizienten Transfektion des DNAzyms. Alle PEI-PEG Polymere zeigten dabei eine deutlich geringere Zytoxizität als unmodifiziertes PEI. Das PEI(25kDa)-g-PEG(5kDa)4 Molekül mit vier 5 kDa PEG-Seitenketten zeigte unter den untersuchten PEI-PEG Molekülen die höchste Transfektionseffizienz, so dass dieses für einen initialen in vivo Versuch ausgewählt wurde. In diesem Experiment wurde Mäusen mit einem experimentell induzierten Asthma Phänotyp einmal täglich über vier Tage parallel zur lokalen Allergenprovokation ein Komplex aus GATA-3 spezifischem DNAzym und PEI-PEG Polymer intratrachael verabreicht. Dieses Protokoll führte jedoch zu einer schweren, bei einigen Tieren sogar letalen Entzündung der Lunge. Der Effekt war dabei abhängig von der Menge des verabreichten Polymers und am ausgeprägtesten in den Tieren, die unkomplexiertes PEI-PEG ohne DNAzym erhielten. Die von uns untersuchten DNAzym/PEI-PEG Komplexe erwiesen sich, ähnlich wie bereits beschriebene siRNA/PEI-PEG Komplexe, als effektive Vektoren in vitro. Die beobachteten Nebenwirkungen in vivo deuten jedoch auf eine nicht unerhebliche Toxizität dieser Komplexe hin. Da für den Einsatz in der chronischen Erkrankung Asthma bronchiale von längeren Therapiezeiträumen auszugehen ist, sind dafür jedoch besonders gut verträgliche therapeutische Systeme erforderlich. Daher muss die weitere Entwicklung von Vektorsystemen für die lokale Applikation nukleinsäure-basierter Therapeutika zum Ziel haben, die toxischen Eigenschaften dieser Komplexe bei gleichen oder gar noch weiter verbesserten in vivo Transfektionseffizienzen signifikant zu reduzieren.

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