An esterase-activated diketopyrrolopyrrole-based theranostic prodrug for precise pyroptosis and synergistic chemo-photodynamic therapy of pancreatic cancer

Abstract

Pyroptosis, a novel form of programmed cell death, has demonstrated significant antitumor effects. However, enhancing the precision of pyroptosis and improving the treatment efficacy for malignant tumors still remain formidable challenges. In this work, we propose a novel synergistic chemo-photodynamic therapy strategy that targets endogenous esterase in the tumor microenvironment (TME), aiming to achieve precise pyroptosis and facilitate the release of chemotherapeutic drugs to promote pyroptosis. An esterase-activated diketopyrrolopyrrole-based theranostic prodrug DPP-QS was synthesized by the conjugation of a chemotherapeutic drug chlorambucil, with DPP-QE characteristic of aggregation-induced emission (AIE) through a one-step nucleophilic reaction. Besides, the detection limit of DPP-QS toward esterase in vitro was 5.13 × 10⁻⁵ U mL⁻¹. Upon cleavage by esterase endogenously expressed in pancreatic cancer cells, the released DPP-QE moiety selectively accumulated in lipid droplets (LDs) with a significantly enhanced fluorescence due to AIE, and upon subsequent exposure to light, reactive oxygen species (ROS) are generated to induce pyroptosis. Simultaneously, chlorambucil entered the nucleus of cancer cells, causing DNA damage, which further enhanced the effect of pyroptosis. In vivo experiments demonstrated that the prodrug displayed significant TME-activatable features and excellent tumor therapeutic effects through synergistic chemo-photodynamic therapy.