Tumor-targeted activatable molecular agent for synergistic chemo-photodynamic therapy

The combination of photodynamic therapy (PDT) and chemotherapy offers a promising strategy to enhance cancer treatment efficacy. Herein, we report the design and synthesis of TBBS-CPT, a tumor-targeted, unimolecular therapeutic agent that covalently integrates a camptothecin (CPT) chemotherapeutic motif and a photosensitizer module via a glutathione (GSH)-cleavable disulfide linker, further modified with a biotin ligand for tumor targeting. In vitro characterization and cellular studies demonstrated that TBBS-CPT acts as an activatable prodrug, efficiently releasing both CPT and the photosensitizer in response to intracellular GSH, thereby inducing a potent chemo-photodynamic synergistic cytotoxic effect against 4 T1 tumor cells. The conjugate exhibited selective accumulation in biotin receptor-positive tumor cells and preferential localization within mitochondria. In vivo studies further confirmed the tumor-specific accumulation of TBBS-CPT and its enhanced therapeutic efficacy through the combination of chemotherapy and PDT in 4 T1 tumor-bearing mice. Collectively, these findings highlight TBBS-CPT as a promising tumor-targeted activatable therapeutic agent capable of integrating controlled drug release and synergistic chemo-photodynamic therapy for precise cancer treatment.