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Size-transformable nanoparticles with sequentially triggered drug release and enhanced penetration for anticancer therapy

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Abstract

There are several limitations to the application of nanoparticles in the treatment of cancer, including their low drug loading, poor colloidal stability, insufficient tumor penetration, and uncontrolled release of the drug. Herein, gelatin/laponite (LP)/doxorubicin (GLD) nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery. GLD shows high doxorubicin encapsulation efficacy (99%) and strong colloidal stability, as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles. When gelatin from 115 nm GLD reaches the tumor site, matrix metallopeptidase-2 (MMP-2) from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis. As demonstrated by superior penetration in both in vitro three-dimensional (3D) tumor spheroids (138-fold increase compared to the free drug) and in vivo tumor models. The intracellular low pH and MMP- 2 further cause doxorubicin release after endocytosis by tumor cells, leading to a higher inhibitory potential against cancer cells. The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model. MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD, offering a useful method for anticancer therapy.

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Acknowledgments

This research was supported by the National Basic Research Program of China (973 Program, No. 2012CB933600), the National Natural Science Foundation of China (Nos. 81771964 and 82072051) and the Shanghai Municipal Natural Science Foundation (No. 15ZR1408500). This work was funded by the Special Project of Clinical Research of Health Industry of Shanghai Municipal Health Commission (No. 201940178), the Scientific Research Project of Hongkou District Health Committee of Shanghai (No. 2002-17), the Clinical Research Project of Wu Jieping Medical Foundation (No. 320.6750.2020-18-2), and the Research Project of Shanghai Fourth People’s Hospital (No. sykyqd 00701 & 00702).

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  1. Yulin Li, Liudi Wang, GuoqiangZhong, Guoying Wang, and Yanzhao Zhu contributed equally to this work.

Authors and Affiliations

  1. Engineering Research Centre for Biomedical Materials of Ministry of Education, The Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Material Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China

    Yulin Li, Liudi Wang, Guoqiang Zhong & Guoying Wang

  2. Department of Oncology Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, China

    Jian Li & Kaichun Li

  3. Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Jie Gao

  4. College of Life Sciences Mudanjiang Medical University, Mudanjiang, 157011, China

    Yanzhao Zhu, Yanhui Chu & Yan Wu

  5. Wenzhou Institute of Shanghai University, Wenzhou, 325000, China

    Yulin Li

  6. Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD, 4059, Australia

    Lan Xiao

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  1. Yulin Li
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Correspondence to Yulin Li, Yan Wu, Kaichun Li or Jie Gao.

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Size-transformable nanoparticles with sequentially triggered drug release and enhanced penetration for anticancer therapy

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Li, Y., Wang, L., Zhong, G. et al. Size-transformable nanoparticles with sequentially triggered drug release and enhanced penetration for anticancer therapy. Nano Res. 16, 11186–11196 (2023). https://doi.org/10.1007/s12274-023-5833-5

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