posted on 2023-08-09, 17:36authored bySandra Deiser, Marike Drexler, Guillermo Moreno-Alcántar, Maximilian Irl, Claudia Schmidt, Thomas Günther, Angela Casini
Self-assembled supramolecular coordination complexes
(SCCs) hold
promise for biomedical applications in cancer therapy, although their
potential in the field of nuclear medicine is still substantially
unexplored. Therefore, in this study an exo-functionalized
cationic [Pd2L2]4+ metallacycle (L
= 3,5-bis(3-ethynylpyridine)phenyl), targeted to the somatostatin-2
receptor (sst2R) and featuring the DOTA chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid) in order to bind the β–- and γ-emitter
lutetium-177, was synthesized by self-assembly following ligand synthesis
via standard solid-phase peptide synthesis (SPPS). This metallacycle
was then characterized by reverse-phase high-performance liquid chromatography
(RP-HPLC), electrospray ionization mass spectrometry (ESI-MS), and 1H and 1H-DOSY NMR (DOSY = diffusion-ordered spectroscopy).
A procedure for the radiolabeling of the metallacycle with 177Lu was also optimized. The resulting [nat/177Lu]Lu-DOTA-metallacycle,
termed [nat/177Lu]Lu-Cy, was evaluated concerning
its stability and in vitro properties. The compound
was more lipophilic compared to the reference [177Lu]Lu-DOTA-TATE
(logPOct/H2O = −0.85
± 0.10 versus −3.67 ± 0.04, respectively). While
[natLu]Lu-Cy revealed low stability in a DMEM/F12
GlutaMax medium, it demonstrated good stability in other aqueous media
as well as in DMSO. A high sst2R binding affinity (expressed as IC50) was determined in CHOsst2 cells (Chinese hamster
ovary cells that were stably transfected with human sst2R). Moreover,
the metallacycle exhibited high human serum albumin binding, as assessed
by high-performance affinity chromatography (HPAC), and moderate stability
in human serum compared to [177Lu]Lu-DOTA-TATE (TATE =
(Tyr3)-octreotate). In order to improve stability, a heteroleptic
approach was used to develop a less sterically hindered cage-like
SCC that is potentially endowed with host–guest chemistry capability,
which has been preliminarily characterized by RP-HPLC and ESI-MS.
Overall, our initial results encourage future studies on sst2R-directed
SCCs and have led to new insights into the chemistry of ss2R-directed
SCCs for radiopharmaceutical applications.