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

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 molecule. 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.