Glutathione-Responsive Nano-Prodrug Mediates Synergistic Photothermal Chemotherapy for Tumor Inhibition

Abstract Photothermal therapy (PTT) offers the advantages of noninvasiveness and high selectivity, while chemotherapy shows potent antitumor activity. However, their standalone applications are limited by insufficient photothermal ablation efficacy and chemotherapeutic resistance, respectively. To address these challenges, we developed a novel boron dipyrromethene (BODIPY)-based scaffold featuring “barrier-free” rotators and an intramolecular charge-transfer (ICT) effect to enhance photothermal performance. Two chlorambucil (CLB) molecules were conjugated to the scaffold via a glutathione (GSH)-sensitive disulfide linker. The resulting prodrug was further encapsulated by an amphiphilic mPEG-b-PCL copolymer to construct a nanoplatform that integrates efficient photothermal therapy with tumor microenvironment-responsive drug release. Both in vitro and in vivo studies confirmed selective tumor accumulation through the enhanced permeability and retention (EPR) effect, significant tumor growth inhibition upon laser irradiation, and low systemic toxicity. This work provides a promising strategy for effective and safe combination photothermal chemotherapy.