Fabritz, Sebastian (2013)
Bioconjugation of Peptides on Cube-octameric Silsesquioxanes.
Technische Universität Darmstadt
Dissertation, Erstveröffentlichung

Kurzbeschreibung (Abstract)

In the present thesis the development of new, efficient and bioorthogonal conjugation methods for the derivatization of cube-octameric silsesquioxanes (COSS) is described. The successful synthesis of an octaazide COSS scaffold allowed for the eightfold conjugation of an octa-RGD peptide via copper(I)-catalyzed alkyne-azide [3+2] cycloaddition (CuAAC) in a water-free system.

As COSS cages are stable in acidic media and aldehydes are easily addressable in this environment, aminooxy-functionalized silsesquioxane derivatives promise high reaction rates upon oxime ligation. Thus, pendant aminooxy groups were introduced into an octaamino COSS precursor by amide coupling with protected aminooxy acetic acid. The subsequent oximation allowed the efficient conjugation with a number of peptidic molecules having up to 35 amino acids in their backbones, among them functional peptides as [KVSALKE]5 or disulfide-rich miniproteins. The number of attached ligands was not only dependent on the reaction rate, but was also dictated by the steric and electrostatic repulsion of the ligands.

Thus, this work showed different experimental approaches to the synthesis of biofunctionalized COSS. Furthermore, a peptide-COSS conjugate was used to demonstrate the possibility to address a central cellular process (DNA replication in higher cells), showing the great application potential of these nanoparticles. Additionally, a preparatory approach is described that might allow for the synthesis of alcohol- and aldehyde-derivatized COSS particles via biotransformation of halogenated silsesquioxanes using haloalkane dehalogenases.

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