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A biodegradable nanodrug with highly efficient treatment effect by remodeling tumor microenvironment and manipulating energy metabolism against colorectal cancer

可生物降解纳米药物通过重塑肿瘤微环境和调节能 量代谢高效治疗结直肠癌

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Abstract

Cisplatin (CDDP), a widely used chemotherapy drug for colorectal cancer, suffers from rapid clearance, resistance, and nonspecific delivery. Meanwhile, the sophisticated tumor microenvironments (TME), such as hypoxia, elevated glutathione (GSH) level, and rapid energy metabolism, result in an unsatisfactory treatment effectiveness of chemotherapy. Herein, a TME-responsive nanoplatform was constructed by loading CDDP and coating with a manganese dioxide (MnO2) shell on the zeolitic imidazolate framework, and finally modified with hyaluronic acid (HA) as a targeting molecule (ZIF-90@CDDP@MnO2@HA) for the combined chemotherapy/chemodynamic therapy (CDT)/starvation therapy of colorectal cancer. The TME-responsive drug release significantly improves the therapeutic efficacy of chemotherapy. On the one hand, the MnO2 shell depletes GSH to inhibit CDDP detoxification and reactive oxygen species clearance, and the released Mn2+ could achieve CDT. On the other hand, the downregulating expression of hypoxia-inducible transcription factor 1α by oxygen generation not only reverses chemotherapy resistance but also inhibits aerobic glycolysis by downregulating expression of hexokinase 2 and glucose transportase-1, further contributing to starvation therapy. In addition, Zn2+ released from ZIF-90 causes mitochondrial damage, further inhibiting adenosine triphosphate production in concert with glycolysis inhibition to enhance starvation therapy. This synergistic treatment strategy exhibits an excellent antitumor effect in vitro and in vivo, which opens a new way to enhance the antitumor efficacy of CDDP-based chemotherapy for colorectal cancer.

摘要

顺铂(CDDP)是治疗结直肠癌的常用化疗药物, 但其存在清除 快、耐药和靶向性差等问题. 同时, 缺氧、高水平谷胱甘肽和快速能量 代谢等复杂的肿瘤微环境, 也是导致化疗疗效不理想的原因之一. 本文 首先在沸石咪唑框架上负载CDDP, 而后在表面包裹二氧化锰外壳, 最 后以透明质酸(HA)作为靶向分子进行修饰, 成功构建了一种肿瘤微环 境响应型纳米平台(ZIF-90@CDDP@MnO 2 @HA), 实现了化疗、化学动 力学疗法和饥饿疗法的联合治疗. 肿瘤微环境响应性药物释放大大提 高了化疗的疗效. MnO2 外壳一方面会消耗谷胱甘肽(GSH)以抑制 CDDP解毒和活性氧(ROS)清除, 同时, 释放的Mn2+ 可实现化学动力治 疗. 另一方面, MnO2 通过原位氧气生成下调低氧诱导转录因子1α的表 达, 不仅能提高化疗耐受性, 还能通过下调己糖激酶2和葡萄糖转运蛋 白1的表达, 抑制有氧糖酵解, 进一步促进饥饿疗法. 此外, ZIF-90释放 的Zn2+ 会造成线粒体损伤, 进一步抑制三磷酸腺苷(ATP)的产生, 从而 加强饥饿疗法. 这种协同治疗策略在体外和体内均表现出良好的抗肿 瘤效果, 为结直肠癌联合治疗开辟了一条新途径.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (52072142) and the Program of Science and Technology Development Plan of Jilin Province of China (20230508071RC).

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Authors and Affiliations

  1. Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China

    Shaopeng Zhang  (张绍鹏), Peizhe Song  (宋沛哲), Wei Li  (李伟) & Daguang Wang  (王大广)

  2. State Key Laboratory of Rare Earth Resource Utilization; Changchun Institute of Applied Chemistry (CIAC), Chinese Academy of Sciences (CAS), Changchun, 130022, China

    Hao Zhang  (张昊), Yinghui Wang  (王樱蕙) & Hongjie Zhang  (张洪杰)

  3. Department of Neurosurgery, The First Hospital of Jilin University, Changchun, 130021, China

    Yue Cao  (曹悦)

  4. Department of Chemistry, Tsinghua University, Beijing, 100084, China

    Hongjie Zhang  (张洪杰)

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  1. Shaopeng Zhang  (张绍鹏)
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  2. Hao Zhang  (张昊)
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  6. Daguang Wang  (王大广)
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Contributions

Author contributions Zhang S, Wang Y, and Wang D conceived and designed the experiments. Zhang S, Zhang H, Song P, Cao Y, and Li W performed the experiments. Zhang S and Zhang H collected and analyzed the data. Zhang S and Wang Y wrote the paper. All authors contributed to the general discussion.

Corresponding authors

Correspondence to Daguang Wang  (王大广), Yinghui Wang  (王樱蕙) or Hongjie Zhang  (张洪杰).

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Conflict of interest The authors declare that they have no conflict of interest.

Additional information

Supplementary information The supporting data are available in the online version of the paper.

Shaopeng Zhang is now studying at the First Hospital of Jilin University for a doctoral degree, majoring in general surgery. His main research direction is biomaterials and oncology.

Daguang Wang is a professor and chief physician, deputy director of the Department of Gastrocolorectal Surgery, First Hospital of Jilin University. He earned his MD degree from the Department of Gastrocolorectal Surgery, First Hospital of Jilin University. Afterwards, he was a visiting scholar at the Molecular Pathology Laboratory, Department of Pathology, Mount Sinai School of Medicine, USA in 2008. Then he worked as a visiting scholar at Minimally Invasive Surgery, Ohio State University College of Medicine, USA in 2015, and as a clinical trainer at Cancer Research Ariake Hospital, Japan in 2018. His research focuses on the minimally invasive surgical treatment of gastrointestinal tumors and bioinformatics, cell signaling in gastrointestinal tumors, functional nanomaterials in gastrointestinal tumors, and surgical nutrition support and metabolomics.

Yinghui Wang received her PhD degree in condensed matter physics from Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences (CAS) in 2011. Then, she worked as a postdoctoral researcher at the University of Amsterdam (Netherlands) and Changchun Institute of Applied Chemistry, CAS. She is working as a professor at Changchun Institute of Applied Chemistry, CAS. Her research interests focus on the design and synthesis of multifunctional nanoparticles and their bioapplications.

Hongjie Zhang received his BS degree from Peking University (1978) and MS degree from Changchun Institute of Applied Chemistry, CAS (1985). Then, he worked as an assistant professor at the same institute from 1985 to 1989. He then studied at the University of Bordeaux I (France), where he received his PhD degree in 1993. In 1994, he joined Changchun Institute of Applied Chemistry, CAS, as a professor. He was elected as an academician of the CAS in 2013, and a member of The World Academy of Sciences (TWAS) in 2015. His current research interests include the synthesis and application of lanthanide functional materials.

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40843_2023_2693_MOESM1_ESM.pdf

A biodegradable nanodrug with highly efficient treatment effect by remodeling tumor microenvironment and manipulating energy metabolism against colorectal cancer

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Zhang, S., Zhang, H., Song, P. et al. A biodegradable nanodrug with highly efficient treatment effect by remodeling tumor microenvironment and manipulating energy metabolism against colorectal cancer. Sci. China Mater. 67, 331–342 (2024). https://doi.org/10.1007/s40843-023-2693-7

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