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Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance

Nature Biomedical Engineering volume 5, pages 1048–1058 (2021)Cite this article

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Abstract

In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.

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Fig. 1: Synthesis of the reduction-responsive polymer and formation of NPs.
Fig. 2: Characterization of NPs.
Fig. 3: Intracellular uptake of dye-loaded NPs.
Fig. 4: NP-OxaPt(iv) and NP-56MESS inhibit the growth of GBM cells.
Fig. 5: Antitumour efficacies of NP-OxaPt(iv) and NP-56MESS in mice bearing LN229-TR-LUC tumours.
Fig. 6: Transcriptional analysis of LN229 cells treated with TMZ, 56MESS and NP-56MESS.
Fig. 7: Analysis of metabolic pathways in LN229-TS cells treated with TMZ, 56MESS and NP-56MESS.

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Data availability

The authors declare that the main data supporting the findings of this study are available within the paper and its Supplementary Information. The raw data generated for the RNA-seq analysis are available from the NCBI SRA database under the accession code PRJNA668337. The metabolomic dataset generated during the study is too large (2.3 GB) to be publicly shared, but the data are available for research purposes from the corresponding authors on reasonable request.

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Acknowledgements

This work was funded by grants from the US National Institutes of Health (CA149128 to W.M.S.), the National Natural Science Foundation of China (51873218 to H.X.), the National Science and Technology Major Project (2018ZX10734401 to H.X.), the Beijing Natural Science Foundation (2202071 to H.X.), and the Key Research and Development Program of Hunan Province (2019SK2251 to H.X.). A.S.P.-D. was supported by fellowships from NIH (T32 GM86287 and F32 HL142144) and the Cystic Fibrosis Foundation (PIOTRO20F0). A.J. was supported by a fellowship from the US National Science Foundation. We thank J. Ding for providing luciferase vectors.

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Authors and Affiliations

  1. Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China

    Yongheng Wang, Dengshuai Wei & Haihua Xiao

  2. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    Yongheng Wang, Yuhang Jiang, Priya Singh, Teresa Lee, Hanna K. Mandl, Alexandra S. Piotrowski-Daspit, Alexander Josowitz, Fan Yang & W. Mark Saltzman

  3. University of Chinese Academy of Sciences, Beijing, China

    Dengshuai Wei, Xing Li, Fuyi Wang, Zhenwen Zhao & Haihua Xiao

  4. Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China

    Yingjie Yu

  5. College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China

    Lingpu Zhang

  6. Department of Statistics and Data Science, Yale University, New Haven, CT, USA

    Xinyuan Chen & Fan Li

  7. Center for Methods in Implementation and Prevention Science, Yale University, New Haven, CT, USA

    Fan Li

  8. National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China

    Xing Li, Yiyu Cheng, Yao Zhao, Fuyi Wang & Zhenwen Zhao

  9. Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, China

    Yiyu Cheng

  10. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    Anita Huttner & Ranjit S. Bindra

  11. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA

    Ranjit S. Bindra

  12. Department of Chemical and Environmental Engineering, Yale University, New Haven, CT, USA

    W. Mark Saltzman

  13. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA

    W. Mark Saltzman

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  1. Yongheng Wang
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Contributions

Y.W., R.S.B., H.X. and W.M.S. discussed and designed the study. D.W., Y.Y. and L.Z. prepared and characterized the polymer and drugs. P.S. and T.L. helped conduct the cell viability assays. H.K.M. assisted in analysing the flow cytometry data. A.S.P.-D. helped perform toxicity experiments. A.H. analysed the haematoxylin and eosin images from the brain. X.L. and Z.Z. aided in the metabolome analysis. A.J., Y.C., Y.Z., P.S. and F.W. contributed to characterization of NPs. X.C. and F.L. helped with the statistical analysis. Y.W. and Y.J. conducted all other experiments in this manuscript. All authors discussed the data and reviewed the manuscript.

Corresponding authors

Correspondence to Haihua Xiao or W. Mark Saltzman.

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Peer review information Nature Biomedical Engineering thanks Shiv Gupta and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary figures.

Reporting Summary

Supplementary Dataset 1

Gene information for Fig. 6a.

Supplementary Dataset 2

P values for comparisons conducted in Fig. 4.

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Wang, Y., Jiang, Y., Wei, D. et al. Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance. Nat Biomed Eng 5, 1048–1058 (2021). https://doi.org/10.1038/s41551-021-00728-7

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