Treatment of glioblastoma multiforme cells with temozolomide-BioShuttle ligated by the inverse Diels-Alder ligation chemistry

Original Research

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Authors: Klaus Braun, Manfred Wiessler, Volker Ehemann, Ruediger Pipkorn, Herbert Spring, et al

Published Date January 2009 Volume 2008:2 Pages 289 - 301

DOI: http://dx.doi.org/10.2147/DDDT.S3572

Klaus Braun¹, Manfred Wiessler¹, Volker Ehemann², Ruediger Pipkorn³, Herbert Spring⁴, Juergen Debus⁵, Bernd Didinger⁵, Mario Koch³, Gabriele Muller⁶, Waldemar Waldeck⁶

¹German Cancer Research Center, Dept of Imaging and Radiooncology, Heidelberg, Germany; ²University of Heidelberg, Institute of Pathology, Heidelberg, Germany; ³German Cancer Research Center, Central Peptide Synthesis Unit, Heidelberg, Germany; ⁴German Cancer Research Center, Dept of Structural Analysis of Gene Structure and Function, Heidelberg, Germany; ⁵University of Heidelberg, Dept of Radiation Oncology, Heidelberg, Germany; ⁶German Cancer Research Center,Division of Biophysics of Macromolecules, Heidelberg, Germany

Abstract: Recurrent glioblastoma multiforme (GBM), insensitive against most therapeutic interventions, has low response and survival rates. Temozolomide (TMZ) was approved for second-line therapy of recurrent anaplastic astrocytoma. However, TMZ therapy in GBM patients reveals properties such as reduced tolerability and inauspicious hemogram. The solution addressed here concerning GBM therapy consolidates and uses the potential of organic and peptide chemistry with molecular medicine. We enhanced the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic TMZ. The TMZ connection to transporter molecules (TMZ-BioShuttle) was investigated, resulting in a much higher pharmacological effect in glioma cell lines and also with reduced dose rate. From this result we can conclude that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The TMZ-BioShuttle dramatically enhanced the potential of TMZ for the treatment of brain tumors and is an attractive drug for combination chemotherapy.

Keywords: drug delivery, carrier molecules, facilitated transport, glioblastoma multiforme, temozolomide