Histone Deacetylase-Triggered Self-Immolative Peptide-Cytotoxins for Cancer-Selective Drug Delivery |
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Authors: | Haoyu Bai Huifang Wang Zhuha Zhou Ying Piao Xiangrui Liu Jianbin Tang Xian Shen Youqing Shen Zhuxian Zhou |
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Affiliation: | 1. Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027 China;2. Department of Gastroenterological Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035 China |
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Abstract: | Precise delivery and release of therapeutics in the subcellular targets are critical for tumor-selective chemotherapy. Self-immolative structures are sophisticatedly designed to achieve stimuli-responsive drug delivery. Herein, the facile fabrication of self-immolative peptide-camptothecin (CPT) nanoassemblies is reported for cancer-selective drug delivery by utilizing the dual-mode peptide targeting design and amine-catalyzed intramolecular hydrolysis. The dual-mode peptide targeting design is realized by co-assembly of tumor targeting and nuclei-localizing peptide-CPT prodrugs, rendering the nanoassemblies with efficient cancer cell-selective capability. When the nanoassemblies enter cancer cell, the overexpressed endonuclear histone deacetylases (HDACs) cleave the acetyl group to generate primary amines, triggers amine-catalyzed intramolecular hydrolysis, and fast-release drug in the cell nuclei. The peptide-CPT prodrugs release up to 68% CPT in 1 h in the presence of HDACs, while no detectable CPT release is observed in the absence of HDACs at the same time. The peptide-CPT prodrugs selectively kill cancer cells with high HDACs levels. The dual targeting peptide-CPT nanoassemblies exhibit extended blood circulation, excellent tumor accumulation, and potent antitumor activity by inhibiting tumor progression and metastasis in mice bearing 4T1 aggressive breast tumors. Overall, the HDAC-triggered self-immolative strategy is promising for developing cancer-selective drug delivery systems. |
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Keywords: | camptothecin prodrugs histone deacetylase (HDAC)-responsive peptide-drug conjugates self-immolative tumor-targeting peptides |
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