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Research Article

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

Yulin Li1,5,§( ), Liudi Wang1,§, Guoqiang Zhong1,§, Guoying Wang1,§, Yanzhao Zhu4,§, Jian Li2, Lan Xiao6, Yanhui Chu4, Yan Wu4( ), Kaichun Li2( ), Jie Gao3( )
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
Department of Oncology Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, China
Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China
College of Life Sciences Mudanjiang Medical University, Mudanjiang 157011, China
Wenzhou Institute of Shanghai University, Wenzhou 325000, China
Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia

§ Yulin Li, Liudi Wang, Guoqiang Zhong, Guoying Wang, and Yanzhao Zhu contributed equally to this work.

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Graphical Abstract

By crosslinking laponite (LP) with gelatin for doxorubicin delivery, gelatin/laponite/doxorubicin (GLD) nanoparticles are developed. They show strong colloidal stability and reduced protein absorption, as demonstrated by superior penetration in both in vitro three-dimensional (3D) tumor spheroids and in vivo tumor models. The intracellular low pH and matrix metallopeptidase-2 (MMP-2) further cause doxorubicin release after endocytosis by tumor cells, leading to a higher inhibitory potential against cancer cells.

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.

Keywords

nanoparticlesdrug deliverytumor penetrationanticancer therapysequentially triggered drug releasesize-transformable

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Nano Research
Volume 16 Issue 8,
August 2023
Pages 11186-11196
DOI: 10.1007/s12274-023-5833-5
Cite this article:
Li Y, Wang L, Zhong G, et al. Size-transformable nanoparticles with sequentially triggered drug release and enhanced penetration for anticancer therapy. Nano Research, 2023, 16(8): 11186-11196. https://doi.org/10.1007/s12274-023-5833-5
Topics:
Drug delivery

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Received: 01 March 2023
Revised: 09 May 2023
Accepted: 11 May 2023
Published: 25 July 2023
© Tsinghua University Press 2023
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