Nano-sensitizer with self-amplified drug release and hypoxia normalization properties potentiates efficient chemoradiotherapy of pancreatic cancer

• Published in: Biomaterials 2024-10, Vol.310, p.122634, Article 122634
• Main Authors: Yu, Shuchen, Jiang, Yitong, Li, Qian, Li, Mengmeng, Su, Jiamin, Lai, Shicong, Gan, Zhihua, Ding, Zhenshan, Yu, Qingsong
• Format: Article
• Language: English
• Subjects: Akt inhibition; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; biocompatible materials; Cell Line, Tumor; Chemoradiotherapy; Chemoradiotherapy - methods; Drug Liberation; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; hypoxia; Hypoxia heterogeneity; Hypoxia normalization; metronidazole; Metronidazole - pharmacology; Metronidazole - therapeutic use; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles - chemistry; NQO1; oxygen; pancreatic neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; polymers; quinones; radiotherapy; Tirapazamine - pharmacology; Tumor Hypoxia - drug effects; Tumor Microenvironment - drug effects
• ISSN: 0142-9612; 1878-5905; 1878-5905
• DOI: 10.1016/j.biomaterials.2024.122634

The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia—primarily caused by limited oxygen penetration—has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution. [Display omitted] •KP372-1 normalizes the hypoxia distribution through NQO-1 mediated mechanism.•Hypoxia normalization triggers self-amplified drug release.•The nano -sensitizer efficiently sensitizes chemoradiotherapy under all conditions.•Akt inhibition further strengthens the efficacy of chemoradiotherapy.