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Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion–drug conjugates with cell-membrane affinity

Nature Biomedical Engineering volume 5, pages 1019–1037 (2021)Cite this article

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Abstract

Effective anticancer nanomedicines need to exhibit prolonged circulation in blood, to extravasate and accumulate in tumours, and to be taken up by tumour cells. These contrasting criteria for persistent circulation and cell-membrane affinity have often led to complex nanoparticle designs with hampered clinical translatability. Here, we show that conjugates of small-molecule anticancer drugs with the polyzwitterion poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) have long blood-circulation half-lives and bind reversibly to cell membranes, owing to the negligible interaction of the polyzwitterion with proteins and its weak interaction with phospholipids. Adsorption of the polyzwitterion–drug conjugates to tumour endothelial cells and then to cancer cells favoured their transcytosis-mediated extravasation into tumour interstitium and infiltration into tumours, and led to the eradication of large tumours and patient-derived tumour xenografts in mice. The simplicity and potency of the polyzwitterion–drug conjugates should facilitate the design of translational anticancer nanomedicines.

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Fig. 1: OPDEA-based conjugate or block copolymer with the anticancer drug SN38 and the drug delivery process.
Fig. 2: In vitro cellular internalization of OPDEA.
Fig. 3: In vivo blood clearance of OPDEA-SN38 and OPDEA-PSN38.
Fig. 4: In vitro tumour penetration and in vivo tumour extravasation of OPDEA.
Fig. 5: In vivo tumour penetration of OPDEA.
Fig. 6: In vitro and in vivo anticancer activity of OPDEA conjugate and micelles.
Fig. 7: Mechanistic studies of RBC binding- and active transcytosis-based trans-endothelial transportation of OPDEA.
Fig. 8: The effects of inhibitors of endo- and exocytosis on the penetration of RhoBOPDEA in HepG2 or HT29 spheroids.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

This work received support from the National Natural Science Foundation (51833008) of China and Zhejiang Key Research Program (2020C01123). We thank H. Cui of Johns Hopkins University for his generous instructions and help, and H. Xu for the design of the scheme in Fig. 1. We acknowledge support from the Bio-ultrastructure Analysis Laboratory of the Analysis Center of Agrobiology and Environmental Science of Zhejiang University in sample preparation and transmission electron microscopy.

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  1. These authors contributed equally: Siqin Chen, Yin Zhong, Wufa Fan, Jiajia Xiang.

Authors and Affiliations

  1. Zhejiang Key Laboratory of Smart BioMaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China

    Siqin Chen, Yin Zhong, Wufa Fan, Jiajia Xiang, Guowei Wang, Quan Zhou, Jinqiang Wang, Yu Geng, Rui Sun, Zhen Zhang, Ying Piao, Zhuxian Zhou, Jianbin Tang & Youqing Shen

  2. Key Laboratory of Biomass Chemical Engineering of the Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China

    Siqin Chen, Yin Zhong, Wufa Fan, Jiajia Xiang, Guowei Wang, Quan Zhou, Jinqiang Wang, Yu Geng, Rui Sun, Zhen Zhang, Ying Piao, Zhuxian Zhou, Jianbin Tang & Youqing Shen

  3. Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China

    Siqin Chen, Wufa Fan, Jiajia Xiang, Quan Zhou, Yu Geng, Rui Sun, Ying Piao, Zhuxian Zhou & Youqing Shen

  4. Department of Polymer Science and Engineering, Peking University, Beijing, China

    Wufa Fan & Zichen Li

  5. Department of Surgery, First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China

    Jianguo Wang, Jianyong Zhuo & Xiao Xu

  6. Institute of Biomedical Materials and Engineering, College of Materials Science and Engineering, Qingdao University, Qingdao, China

    Hailin Cong

  7. Department of Medical Oncology, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China

    Haiping Jiang

  8. Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China

    Jun Ling

  9. School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, China

    Dingding Yang & Xin Yao

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  1. Siqin Chen
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Contributions

Y.S. conceived and supervised the project. S.C., Y.Z., W.F., Q.Z. and Y.P. performed the biological experiments and analysed the data; J.X., Jinqiang Wang, Y.G. and Z. Zhang performed the synthesis; G.W. did the transmission electron microscopy imaging and H&E staining; R.S. did the ITC assay; J.L. performed calculations; Jianguo Wang, J.Z. and X.X. established the PDX models; D.Y. and X.Y. performed the SPR experiment; H.C. and Z.L. helped with discussion of the synthesis and mechanism; H.J., J.T. and Z. Zhou helped with supervision of experiments and writing. All authors discussed the results and participated in writing the manuscript.

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Correspondence to Youqing Shen.

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Peer review information Nature Biomedical Engineering thanks Daryl Drummond and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary Video 1

Cellular internalization of Cy5.5OPDEA by HepG2 cells in vitro.

Supplementary Video 2

Cellular internalization of Cy5.5PEG by HepG2 cells in vitro.

Supplementary Video 3

Real-time in vivo imaging of Cy5.5OPDEA extravasating from tumour blood vessels into tumour tissue.

Supplementary Video 4

Real-time in vivo imaging of Cy5.5PEG extravasating from tumour blood vessels into tumour tissue.

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Chen, S., Zhong, Y., Fan, W. et al. Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion–drug conjugates with cell-membrane affinity. Nat Biomed Eng 5, 1019–1037 (2021). https://doi.org/10.1038/s41551-021-00701-4

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