Furin‐Mediated Intracellular Aggregation of Radioactive Molecules for Enhanced Radionuclide Imaging and Tumor Therapy

ABSTRACT Radiopharmaceutical serves as a “golden key” for accurate disease diagnosis and treatment. However, their clinical application is still impeded by rapid systemic clearance and limited retention within tumor tissues. Therefore, the development of advanced radiopharmaceuticals with good tumor specificity and prolonged intratumoral retention is highly critical for effective tumor imaging and therapy. Herein, we rationally design and synthesize a furin enzyme‐responsive radioactive molecule RVRR‐TPE that consists of a furin enzyme‐specific peptide substrate Arg‐Val‐Arg‐Arg (RVRR), a hydrophobic fluorophore tetraphenylethene (TPE) with aggregation‐induced emission (AIE) characteristics, and a phenol unit for Iodine isotope labeling. Probes RVRR‐TPE were self‐assembled into large nanoparticles in furin enzyme‐positive cancer cells, resulting in enhanced uptake and prolonged retention. In vivo studies demonstrated that the ¹²⁵ I or ¹³¹ I‐labeled probes could be used for Single‐Photon Emission Computed Tomography (SPECT) tumor imaging and significantly suppressed the growth of furin‐positive HCT116 colon tumor with great therapeutic effect. This furin‐mediated aggregation strategy to prolong retention effect offers a promising platform for effective radionuclide imaging and treatment of various malignancies.