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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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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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.
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Supplementary Dataset 1
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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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DOI: https://doi.org/10.1038/s41551-021-00728-7
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