68Ga-Markierungsstrategien für nanodimensionale und polymere Systeme für die Positronen-Emissions-Tomographie
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Abstract
Positrion Emission Tomography (PET) is a non-invasive imaging technique that depicts metabolic processes in the body. With PET it becomes possible to get detailed information about the pharmacokinetics of polymeric and nanodimensional drug delivery systems, in a very elegant way. Therefore, it is absolutely necessary to have a reliable and robust technique to introduce the radioactive nuclide. In the presented work the positron emitting 68Ga was attached to homopolymers, various inorganic nanoparticles and core-crosslinked polymermicelles via different strategies.
One of the used techniques was stain promoted alkyne azide cacloaddiotion (SPAAC), for which the presence of a strained alkyne and an azide is required. The conditions for this reactions are very mild. To have suitable chelating agents for ligation via SPAAC, the chelators DOTA, NODA-GA and DATA were functionalized with either an azide or a strained cycloalkyne. The derivatized chelators were radiolabeled with 68Ga, 44Sc and 177Lu and showed excellent complexation of the respective metal ions. The azide-functionalized chelators showed very good stabilities after complexation of the metal ions, in contrast to the Dibenzylcyclooctyne (DBCO)-derivatized ones. The reason lies here in the lipophilic character of the DBCO, as well as in sterical hindrances.
Polysarcosine homopolymers carrying either an azide or a DBCO as one of their terminal groups were radiolabeled via SPAAC with the chelators described above. The focus was to investigate the radiochemical yields after and before the clickreaction with the particular chelator has taken place. Those reactions are called “direct” and “indirect” radiolabeling. Due to the very mild conditions the indirect strategy is a good and elegant alternative to the direct one. NODA-GA-TEG-azide and DOTA-TEG-azide both showed very good results for the direct and the indirect radiolabeling strategy.
Polymercoated tantalum- and ironoxide nanoparticles were attached to chelators via amide bonding. Therefor the NHS-ester or an in situ generated active ester of DOTA or NODA-GA was used. It was possible to increase the coupling yields if the polymer was coupled to the chelator before it was used for coating. Azide functionalized ironoxide nanoparticles were successfully coupled with [68Ga]Bicyclo[6.1.0]non-4-yne-DOTA in a SPAAC and investigated in a dynamical μPET-measurement, as well as in ex vivo biodistribution studies in healthy mice. The 130 nm sized particles accumulated in liver and spleen and showed good bloodretention.
Micelles formed from PSar-PCys blockcopolymers were core-crosslinked with NODA-GA-liponamide. Radiolabeling with 68Ga followed. Firs in vivo studies were performed and the micelles displayed excellent bloodretention after 60 min.