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ORIGINAL RESEARCH ARTICLE

The Saponin-Mediated Enhanced Uptake of Targeted Saporin-Based Drugs Is Strongly Dependent on the Saponin Structure

Christopher Bachran^*, Mark Sutherland^*,1, Iring Heisler^*, Philipp Hebestreit^,2, Matthias F. Melzig and Hendrik Fuchs^*,3

^* Institut für Klinische Chemie und Pathobiochemie, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany; and Institut für Pharmazie–Pharmazeutische Biologie, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany

To whom requests for reprints should be addressed at ³ Institut für Klinische Chemie und Pathobiochemie, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. E-mail: hendrik.fuchs{at}charite.de

Saponins are a group of plant glycosides consisting of a steroid or triterpenoid aglycone to which one or more sugar chains are attached. They exhibit cell membrane–permeabilizing properties and, thus, have been investigated for their therapeutic potential. Recently, at a nonpermeabilizing concentration saponinum album from Gypsophila paniculata L. has been described to enhance the cytotoxicity of a chimeric toxin in a cell culture model. To elucidate whether this enhancing effect is also mediated by other saponins, we analyzed the ability of seven different saponins to enhance the cytotoxicity of a targeted chimeric toxin. The chimeric toxin is composed of saporin, a plant ribosome-inactivating toxin, a cleavable adapter, and human epidermal growth factor (EGF). Cytotoxicity on EGF receptor (EGFR)-bearing cells was analyzed both alone and after combined application of saponin and chimeric toxin. Only two of the tested saponins, quillajasaponin and saponinum album, enhanced cytotoxicity by more than 1000-fold, whereas the enhancement factors of the other saponins were only approximately 10-fold. In contrast to saponinum album, quillajasaponin enhanced the cytotoxicity both on control cells lacking EGFR and on target cells, indicating that, in this case, the enhancement is not target cell receptor specific. This is also the case for some of the saponins with low enhancement factors. Saponinum album resulted in a more than 13,600-fold receptor-specific enhancement, decreasing the 50% inhibitory concentration (IC₅₀) from 2.4 nM to 0.18 pM, which renders it the best option to promote saporin-3–based drug uptake while retaining specificity for the EGFR.

Key Words: immunotoxin • chimeric toxin • saporin • saponin • triterpenoids • adjuvants