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.

中文翻译：

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一种酯酶激活的基于二酮吡咯并吡咯的治疗诊断前药，用于胰腺癌的精确焦亡和协同化学光动力治疗

细胞焦亡是一种新型的程序性细胞死亡，已显示出显着的抗肿瘤作用。然而，提高焦亡的精准度和提高恶性肿瘤的治疗效果仍然是艰巨的挑战。在这项工作中，我们提出了一种新颖的协同化学光动力治疗策略，以肿瘤微环境（TME）中的内源性酯酶为目标，旨在实现精确的焦亡并促进化疗药物的释放以促进焦亡。通过与化疗药物苯丁酸氮芥结合，合成了一种酯酶激活的基于二酮吡咯并吡咯的治疗诊断前药DPP-QS ，通过一步亲核反应具有聚集诱导发射 (AIE) 的DPP-QE特征。此外， DPP-QS对酯酶的体外检测限为5.13×10 ^-5 U mL ^-1。在被胰腺癌细胞内源表达的酯酶裂解后，释放的DPP-QE部分选择性地积聚在脂滴 (LD) 中，由于 AIE，荧光显着增强，随后暴露在光下时，会产生活性氧 (ROS)，诱发细胞焦亡。同时，苯丁酸氮芥进入癌细胞的细胞核，造成DNA损伤，进一步增强了细胞焦亡的效果。体内实验表明，该前药通过协同化学光动力疗法表现出显着的TME可激活特性和优异的肿瘤治疗效果。