Novel Bifunctional Cyclic Chelator for ⁸⁹Zr Labeling–Radiolabeling and Targeting Properties of RGD Conjugates

Within the last years ⁸⁹Zr has attracted considerable attention as long-lived radionuclide for positron emission tomography (PET) applications. So far desferrioxamine B (DFO) has been mainly used as bifunctional chelating system. Fusarinine C (FSC), having complexing properties comparable to DFO, was expected to be an alternative with potentially higher stability due to its cyclic structure. In this study, as proof of principle, various FSC-RGD conjugates targeting α_vß₃ integrins were synthesized using different conjugation strategies and labeled with ⁸⁹Zr. <i>In vitro</i> stability, biodistribution, and microPET/CT imaging were evaluated using [⁸⁹Zr]­FSC-RGD conjugates or [⁸⁹Zr]­triacetylfusarinine C (TAFC). Quantitative ⁸⁹Zr labeling was achieved within 90 min at room temperature. The distribution coefficients of the different radioligands indicate hydrophilic character. Compared to [⁸⁹Zr]­DFO, [⁸⁹Zr]­FSC derivatives showed excellent <i>in vitro</i> stability and resistance against transchelation in phosphate buffered saline (PBS), ethylenediaminetetraacetic acid solution (EDTA), and human serum for up to 7 days. Cell binding studies and biodistribution as well as microPET/CT imaging experiments showed efficient receptor-specific targeting of [⁸⁹Zr]­FSC-RGD conjugates. No bone uptake was observed analyzing PET images indicating high <i>in vivo</i> stability. These findings indicate that FSC is a highly promising chelator for the development of ⁸⁹Zr-based PET imaging agents

Size Dependent Biodistribution and SPECT Imaging of ¹¹¹In-Labeled Polymersomes

Polymersomes, self-assembled from the block copolymer polybutadiene-<i>block</i>-poly­(ethylene glycol), were prepared with well-defined diameters between 90 and 250 nm. The presence of ∼1% of diethylene triamine penta acetic acid on the polymersome periphery allowed to chelate radioactive ¹¹¹In onto the surface and determine the biodistribution in mice as a function of both the polymersome size and poly­(ethylene glycol) corona thickness (i.e., PEG molecular weight). Doubling the PEG molecular weight from 1 kg/mol to 2 kg/mol did not change the blood circulation half-life significantly. However, the size of the different polymersome samples did have a drastic effect on the blood circulation times. It was found that polymersomes of 120 nm and larger become mostly cleared from the blood within 4 h, presumably due to recognition by the reticuloendothelial system. In contrast, smaller polymersomes of around 90 nm circulated much longer. After 24 h more than 30% of the injected dose was still present in the blood pool. This sharp transition in blood circulation kinetics due to size is much more abrupt than observed for liposomes and was additionally visualized by SPECT/CT imaging. These findings should be considered in the formulation and design of polymersomes for biomedical applications. Size, much more than for liposomes, will influence the pharmacokinetics, and therefore, long circulating preparations should be well below 100 nm