Santos Joana F, Braz Maria T, Raposinho Paula, Cleeren Frederik, Cassells Irwin, Leekens Simon, Cawthorne Christopher, Mendes Filipa, Fernandes Célia, Paulo António
C2TN - Centro de Ciências e Tecnologias Nucleares Instituto Superior Técnico, Universidade de Lisboa, 2695-066 Bobadela LRS, Portugal.
DECN - Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, 2695-066 Bobadela LRS, Portugal.
Mol Pharm. 2024 Jan 1;21(1):216-233. doi: 10.1021/acs.molpharmaceut.3c00787. Epub 2023 Nov 22.
Nuclear DNA is the canonical target for biological damage induced by Auger electrons (AE) in the context of targeted radionuclide therapy (TRT) of cancer, but other subcellular components might also be relevant for this purpose, such as the energized mitochondria of tumor cells. Having this in mind, we have synthesized novel DOTA-based chelators carrying a prostate-specific membrane antigen (PSMA) inhibitor and a triphenyl phosphonium (TPP) group that were used to obtain dual-targeted In-radioconjugates ( and ), aiming to promote a selective uptake of an AE-emitter radiometal (In) by PSMA+ prostate cancer (PCa) cells and an enhanced accumulation in the mitochondria. These dual-targeted In-radiocomplexes are highly stable under physiological conditions and in cell culture media. The complexes showed relatively similar binding affinities toward the PSMA compared to the reference tracer , in line with their high cellular uptake and internalization in PSMA+ PCa cells. The complexes compromised cell survival in a dose-dependent manner and in the case of to a higher extent than observed for the single-targeted congener . μSPECT imaging studies in PSMA+ PCa xenografts showed that the TPP pharmacophore did not interfere with the excellent tumor uptake of the "golden standard" , although it led to a higher kidney retention. Such kidney retention does not necessarily compromise their usefulness as radiotherapeutics due to the short tissue range of the Auger/conversion electrons emitted by In. Overall, our results provide valuable insights into the potential use of mitochondrial targeting by PSMA-based radiocomplexes for efficient use of AE-emitting radionuclides in TRT, giving impetus to extend the studies to other AE-emitting trivalent radiometals (e.g., Tb or Er) and to further optimize the designed dual-targeting constructs.
在癌症的靶向放射性核素治疗（TRT）中，核DNA是俄歇电子（AE）诱导生物损伤的典型靶点，但其他亚细胞成分可能也与此相关，比如肿瘤细胞中充满能量的线粒体。考虑到这一点，我们合成了新型基于DOTA的螯合剂，其带有前列腺特异性膜抗原（PSMA）抑制剂和三苯基鏻（TPP）基团，用于获得双靶向铟放射性缀合物（和），旨在促进PSMA阳性前列腺癌（PCa）细胞对AE发射体放射性金属（铟）的选择性摄取以及在线粒体中的增强积累。这些双靶向铟放射性复合物在生理条件下和细胞培养基中高度稳定。与参考示踪剂相比，这些复合物对PSMA显示出相对相似的结合亲和力，这与它们在PSMA阳性PCa细胞中的高细胞摄取和内化一致。这些复合物以剂量依赖的方式损害细胞存活，并且在的情况下，损害程度比单靶向同类物更高。在PSMA阳性PCa异种移植瘤中的μSPECT成像研究表明，TPP药效基团并不干扰“金标准”的出色肿瘤摄取，尽管它导致更高的肾脏滞留。由于铟发射的俄歇/转换电子的组织射程较短，这种肾脏滞留不一定会损害它们作为放射治疗剂的效用。总体而言，我们的结果为基于PSMA的放射性复合物进行线粒体靶向在TRT中有效利用AE发射放射性核素的潜在用途提供了有价值的见解，推动了将研究扩展到其他发射AE的三价放射性金属（例如，铽或铒）并进一步优化设计的双靶向构建体。
