Enabling AIEgens close assembly in tumor-overexpressed protein cluster for boosted image-guided cancer surgery

Development of efficient fluorescent probes that can realize precise fluorescence image-guided cancer surgery (FIGCS) with extremely high tumor-to-normal tissue (T/NT) ratio is urgently desirable. Herein, we report the design and synthesis of an aggregation-induced emission (AIE)-active, peptide-based fluorescence turn-on probe MPA-Ph-R-FFGYSAYPDSVPMMS (MPA-Ph-R-FFGYSA for short), which consists of a new near-infrared emissive AIE luminogen (AIEgen) MPA-Ph-R, a self-assembling peptide sequence “FFG”, and an “active” targeting peptide YSAYPDSVPMMS that can selectively bind to EphA2 protein cluster overexpressed in many cancers. As compared to the control probe MPA-Ph-R-YSA without “FFG”, MPA-Ph-R-FFGYSA exhibits much higher fluorescent brightness and sensitivity in both cellular and in vivo studies on EphA2 cluster detection/imaging, as “FFG” is beneficial to closer assembly of AIEgens in EphA2 cluster, leading to more effective restriction of the intramolecular motion of AIEgen. In vivo studies demonstrate that MPA-Ph-R-FFGYSA is a safe bioprobe and gives excellent performance in FIGCS with a rather high T/NT ratio of ∼13.4 upon intravenous administration into peritoneal carcinomatosis-bearing mice. This study provides a new strategy of utilizing the close assembly of tumor microenvironment-responsive AIE probes for boost FIGCS.