文献类型：期刊文献

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

作者：Gu, Xixin[1];Yang, Kaini[2];Li, Sifan[1];Mei, Ju[1];He, Xiao-Peng[1];Chen, Wei[2];Hua, Jianli[1]

机构：[1]East China Univ Sci & Technol, Feringa Nobel Prize Scientist Joint Res Ctr, Sch Chem & Mol Engn, Joint Int Res Lab Precis Chem & Mol Engn,Key Lab A, Shanghai 200237, Peoples R China;[2]Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Joint Int Dept Biliary Pancreat Surg,Key Lab Adv M, Shanghai 200127, Peoples R China

年份：2024

卷号：8

期号：8

起止页码：1993

外文期刊名：MATERIALS CHEMISTRY FRONTIERS

收录：;EI(收录号：20241215790675);WOS:【SCI-EXPANDED(收录号:WOS:001187096900001)】；

基金：This work was supported by the National Natural Science Foundation of China (21788102, 22271093, 21971064 and 82102942), the Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX03), the Fundamental Research Funds for the Central Universities (222201717003 and 50321101918001) and the Programme of Introducing Talents of Discipline to Universities (B16017). All of the animal experimental procedures were performed according to the protocols approved by the Animal Care and Use Renji Hospital, School of Medicine, Shanghai Jiaotong University (license no. RJ2023-131A).

语种：英文

外文关键词：Cancer cells - Cell death - Controlled drug delivery - Diseases - Drug products - Enzymes - Esters - Targeted drug delivery - Tumors

摘要：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 x 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. The diketopyrrolopyrrole-based theranostic prodrug (DPP-QS) releases LD-targeted AIE PS (DPP-QE) and drug (chlorambucil) under the cleavage of esterase to achieve precise pyroptosis and chemo-photodynamic therapy of pancreatic cancer.