Evaluation of a Radioiodinated G‐quadruplex Binder in Cervical Cancer Models

Abstract

We herein describe the radiosynthesis of a 125I‐labeled acridine orange derivative ([125I]‐C8), acting as a G‐quadruplex binder, and its biological evaluation in cervical cancer models, aiming to enlighten its potential as a radioligand for Auger Electron Radiopharmaceutical Therapy (AE‐RPT) of cancer. [125I]‐C8 was synthesized with a moderate radiochemical yield (ca. 60 %) by a [125I]iodo‐destannylation reaction. Its evaluation in cervical cancer HeLa cells demonstrated that the radiocompound has a significant cellular internalization with a notorious accumulation in the cell nucleus. In line with these results, [125I]‐C8 strongly compromised the viability of HeLa cells in a dose‐dependent manner, inducing non‐repairable DNA lesions that are most probably due to the AEs emitted by 125I in close proximity to the DNA. Biodistribution studies in a murine HeLa xenograft model showed that [125I]‐C8 has fast blood clearance and high in vivo stability but poor tumor uptake, after systemic administration. The respective supramolecular conjugate with the AS1411 aptamer ([125I]‐C8/AS1411) led to a slower blood clearance in the same animal tumor model, although without improving the tumor uptake. To take advantage of the radiotoxicity of [125I]‐C8 against cervical cancer cells other strategies need to be studied, based namely on alternative nanodelivery carriers and/or intratumoral injection approaches.