Chair of Pharmaceutical Radiochemistry, Department of Chemistry, School of Natural Sciences, Technical University of Munich, Walther-Meißner-Str. 3, 85748 Garching b. München, Germany.
Chair of Medicinal and Bioinorganic Chemistry, Department of Chemistry, School of Natural Sciences, Technical University of Munich, Lichtenbergstr. 4, 85748 Garching b. München, Germany.
Inorg Chem. 2023 Dec 18;62(50):20710-20720. doi: 10.1021/acs.inorgchem.3c02090. Epub 2023 Aug 9.
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 -functionalized cationic [PdL] 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 H and H-DOSY NMR (DOSY = diffusion-ordered spectroscopy). A procedure for the radiolabeling of the metallacycle with Lu was also optimized. The resulting [Lu]Lu-DOTA-metallacycle, termed [Lu]Lu-, was evaluated concerning its stability and properties. The compound was more lipophilic compared to the reference [Lu]Lu-DOTA-TATE (log = -0.85 ± 0.10 versus -3.67 ± 0.04, respectively). While [Lu]Lu- 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 IC) was determined in CHO 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 [Lu]Lu-DOTA-TATE (TATE = (Tyr)-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.
自组装超分子配位化合物（SCCs）在癌症治疗的生物医学应用中具有广阔的前景，尽管它们在核医学领域的潜力仍未得到充分探索。因此，在这项研究中，一种 - 功能化的阳离子[PdL]金属环（L = 3,5-双（3-乙炔基吡啶）苯基），靶向生长抑素-2 受体（sst2R），并具有 DOTA 螯合剂（1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸），以便结合β-和γ发射器镥-177，通过配体合成后通过标准固相肽合成（SPPS）自组装合成。然后通过反相高效液相色谱（RP-HPLC）、电喷雾电离质谱（ESI-MS）和 H 和 H-DOSY NMR（DOSY = 扩散有序光谱）对金属环进行了表征。还优化了金属环与 Lu 的放射性标记过程。所得[Lu]Lu-DOTA-金属环，称为[Lu]Lu-，在其稳定性和特性方面进行了评估。与参考[Lu]Lu-DOTA-TATE（log = -0.85 ± 0.10 对-3.67 ± 0.04）相比，该化合物的亲脂性更高。虽然[Lu]Lu-在 DMEM/F12 GlutaMax 培养基中稳定性较低，但它在其他水性介质以及 DMSO 中表现出良好的稳定性。在 CHO 细胞（稳定转染人 sst2R 的中国仓鼠卵巢细胞）中确定了高 sst2R 结合亲和力（表示为 IC）。此外，通过高效亲和色谱（HPAC）评估，金属环与人血清白蛋白的结合率较高，与[Lu]Lu-DOTA-TATE（TATE =（Tyr）-奥曲肽）相比，其在人血清中的稳定性适中。为了提高稳定性，采用杂配位方法开发了一种空间位阻较小的笼状 SCC，该 SCC 可能具有主体-客体化学能力，其初步通过 RP-HPLC 和 ESI-MS 进行了表征。总的来说，我们的初步结果鼓励对 sst2R 导向 SCCs 进行进一步研究，并对 sst2R 导向 SCCs 的化学性质进行了深入了解，为放射性药物应用提供了新的思路。
