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Entwicklung eines liposomalen Drug Delivery Systems fur die Radiochemotherapie von Tumorgeweben

Entwicklung eines liposomalen Drug Delivery Systems fur die Radiochemotherapie von Tumorgeweben

          
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About the Book

Ziel dieses Promotionsvorhabens war die Etablierung eines liposomalen Drug Delivery Systems zur Kombination der zwei konventionellen Tumortherapiearten Chemo- und Radiotherapie. Dieses System basiert auf einem liposomalen Trager in Kombination mit einem Polyamin-Derivat als molekularen Transporter fur die nanoskalige Verpackung und Solubilisierung von Doxorubicin als Zytostatikum (Doxorubicin-Transporter). Eine saurelabile Wirkstoffkupplung sollte dabei die Wirkstofffreisetzung gezielt in sauren Zellkompartimenten oder Geweben unterstutzen. Gleichzeitig erfolgte die Inkorporierung von Goldnanopartikeln, die als Radiosensitizer unterstutzend zur Bestrahlungstherapie dienen sollen. Angestrebt wurde dabei insbesondere der Einschluss von Doxorubicin-Transporter und Nanopartikeln in die liposomale Membran. Eine gezielte Dimensionierung des liposomalen Systems kann tumorspezifische Anreicherung durch Ausnutzung des EPR-Effektes ermoglichen. Ausgangspunkt war zunachst die Etablierung der einzelnen Teilsysteme, d.h. des liposomalen Doxorubicin-Transporters sowie der liposomalen Goldnanopartikel. Erfolgreiche Inkorporierung, EPR-Effekt geeignete Großen, sowie Stabilitat konnte fur beide Teilsysteme verzeichnet werden. Anschließende Kombination des liposomalen Doxorubicin-Transporters und der liposomalen Goldnanopartikel fuhrte zur Etablierung des liposomalen Drug Delivery Systems. Auch fur dieses konnten EPR-Effekt geeignete Großen und Stabilitat ermittelt werden. Erfolgreicher Transport und intrazellulare lysosomale Anreicherung der Goldnanopartikel in Zellkernnahe konnte sowohl mittels Spinning Disk Konfokalmikroskopie, als auch durch Einbettung und elektronenmikroskopische Betrachtung gezeigt werden. Weiterhin wurde die angestrebte saurelabile Spaltung und Freisetzung des Doxorubicins aus dem Drug Delivery System nach endozytotischer Aufnahme in Zellen erfolgreich nachgewiesen. Mittels eines Toxizitatstests konnte außerdem Schutzwirkung vor den stark toxischen Einflussen des Doxorubicin-Transporters nach liposomaler Inkorporierung beobachtet werden. Dies ist besonders wichtig, um nach in vivo Applikation die Entstehung von Nebenwirkungen zu minimieren. Dennoch konnte mit Hilfe einer Untersuchung der endothelialen Aufnahme und des transendothelialen Transports sehr deutlich gezeigt werden, dass zwar keine schadigenden Einflusse auf das Endothel, jedoch aber auf das darunter liegende Gewebe, in dem das Delivery System angereichert wurde, stattfanden. Auch mittels eines Bestrahlungstests konnte ein Trend zur Erhohung der Bestrahlungswirkung nach Inkorporierung der Goldnanopartikel verzeichnet werden. So konnte insgesamt die erfolgreiche Etablierung eines stabilen liposomalen Drug Delivery Systems, die intrazellulare Anreicherung der transportierten Substanzen in angestrebten Kompartimenten sowie auch Effektivitat des Systems, erreicht werden.


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Product Details
  • ISBN-13: 9783954042807
  • Binding: Paperback
  • Language: German
  • Width: 193 mm
  • ISBN-10: 3954042800
  • Height: 210 mm
  • Weight: 8 gr

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