Synthesis and versatile applications of oligoethylene glycol dendrons using click chemistry

Zusammenfassung

Dendrimers are a class of globular highly branched macromolecules with precise architecture. They consist of a multivalent surface with functional group, a core unit where branching starts, and the interior is made of branching units and the void space in between the branched. Interesting properties of dendrimers are monodispersity, multivalency and a globular geometry. Click chemistry is a ‘set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries’. The most commonly used click reaction is the copper-catalyzed azide-alkyne cycloaddition (CuAAC). Click chemistry is a powerful tool for the construction and functionalization of dendrimers. The principle objective of the present thesis is the use of click chemistry for the synthesis of higher generation dendrons and exploring the possible use of these dendrons for biomedical applications. The first generation dendrons which were synthesized in this work consist of two distinct parts: 1) a core unit derived from the acid diethylene triamine pentaacetic acid (DTPA); 2) monodisperse chains of oligoethylene glycol (OEG) of exact length which are coupled to the DTPA core unit by amide bond formation. The second and third generation dendrons were obtained in two steps: 1) conversion of the surface functional groups to azides; 2) coupling the azide building block unit to the azides of the core unit through CuAAC. Apart from the synthesis of the dendrons using click chemistry, the present thesis also described some biomedical applications of the mentioned dendrons. The core unit derived from DTPA is orthogonally protected and this allows functionalizing the dendrons with distinct moieties. Furthermore, the DTPA derivative endows the dendrons the intrinsic capability to chelate metal ions. The chelation depends on the type of complexated metal ion and also on the functional group in the focal point of the dendron. The metals which can be chelated include gadolinium, terbium and indium, all of which are interesting for medical imaging purposes. Chelating gadolinium with dendrons increase the relaxivity induced by the gadolinium ion because the size of the dendrons slows down the rotation of the metal center. Also, the relaxivity is increased due to the hydrophilic character of the dendrons. Combining the ability to chelate with the multivalency of the dendrons several multimodal platforms for medical imaging were constructed. The platforms were functionalized with targeting peptides and a fluorophore and the DTPA derived core unit carried an isotope of indium. Internalization assays demonstrated that the peptides were able to direct the platforms towards the targeted cells and other preliminary in vivo experiments indicated that the constructs accumulated in the tumors as shown in fluorescence and SPECT imaging. Other dendrons were synthesized to serve as cross-linking agents of bio functionalization platforms. The cross-linking agents were composed of four azides and one bioactive moiety and are used to form hydrogels with the biopolymer hyaluronic acid. The biofunctionalization platforms were composed of four peptides and one azide for coupling the dendron. Using these platforms, peptides sequences could be introduced into the hydrogel and this works to augment the viability of the implanted cells. Finally, an OEG-based dendron was used in combination with carbosilane dendrons to construct hybrid dendrons to bind DNA. The hybrid molecules displayed less cytotoxicity and were more effective delivering genetic material. In conclusion, it has been demonstrated that click chemistry is a powerful tool for the synthesis and versatile applications of OEG-based dendrons.