Macropa-Based 225Ac-Labeled RGD Peptides for Targeted Alpha Therapy
Hiroaki Echigo, Masayuki Munekane, Takeshi Fuchigami, Kenji Mishiro, Hidetoshi Kikunaga, Kazuaki Tsukada, Takuya Yokokita, Kenji Shirasaki, Jun Ichinose, Eiichi Hinoi, Seigo Kinuya, Kazuma OgawaAbstract
Macropa has formed more stable complexes with 225Ac, although DOTA has been extensively used as a chelator for 225Ac. This study aimed to design and synthesize two novel 225Ac-labeled RGD peptides, [225Ac]Ac-Macropa-c(RGDyK) ([225Ac]1) and [225Ac]Ac-Macropa-[c(RGDyK)]2 ([225Ac]2), and to evaluate their potential for targeted alpha therapy (TAT) of glioblastoma. Further, whether combination therapy with homoarginine (hArg), a modulator of lysosomal function, could further improve therapeutic efficacy was investigated. In Colon-26 cells, [225Ac]2 demonstrated significantly higher cellular uptake and cytotoxicity than [225Ac]1. In Colon-26 tumor-bearing mice, [225Ac]2 exhibited higher tumor accumulation and significant tumor growth inhibition. In GL261 glioblastoma cells, [225Ac]2 showed comparable cellular uptake to that in Colon-26 cells, and combination with hArg in vitro improved its cytotoxicity. However, no significant difference in therapeutic efficacy was observed between the hArg-treated and control groups in the orthotopic GL261 glioblastoma mouse model. The results of this study indicate the potential of 225Ac-labeled RGD peptides incorporating Macropa as a chelator as promising agents for TAT. However, the further optimization of combination strategies and pharmacokinetics is required.