FAP-Triggered In Situ Self-Assembly of HPQ in Tumors Empowers 131I Internal Radiotherapy

Abstract Fibroblast activating protein (FAP) is specifically overexpressed in malignant tumors. The 2-(2′-hydroxyphenyl)-4(3H)-quinazolinone (HPQ) scaffold exhibits hydrophobicity, aggregation-induced emission (AIE). The responsive probes built on HPQ can undergo in situ activation and self-assembling precipitation, enabling prolonged retention in lesion sites. Herein, a FAP-cleavable Cbz-Gly-Pro-sequence was conjugated to the phenolic hydroxyl of HPQ via a self-immolative linker, with phenol/tyrosine moieties for 131I labeling through aliphatic linkers, affording LWH-1 and LWH-2. LWH-3 further incorporated a tetraphenylethylene moiety, a PEG6-triazole-PEG6 linker, and (D-Tyr)5-NH2. All precursors for radioiodination responded efficiently to FAP, releasing HPQ-OH to generate AIE and illuminating tumors for over 48 h. [131I]LWH-3 showed a 2.76-fold higher molar activity than [131I]LWH-2 and an in vivo half-life of 43.66 min. In PC12-FAP xenografts, [131I]LWH-3 achieved outstanding antitumor efficacy with favorable biosafety. Transcriptomic and metabolomic analyses revealed that internal radiotherapy attenuated tumor metabolic adaptability by modulating fatty acid metabolism-associated networks to impair proliferation.