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

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.

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.

References

  1. Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459–466 (2009).

    CAS  PubMed  Article  Google Scholar 

  2. Dolecek, T. A., Propp, J. M., Stroup, N. E. & Kruchko, C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol. 14 (Suppl. 5), v1–49 (2012).

  3. Kaina, B., Fritz, G., Mitra, S. & Coquerelle, T. Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells: the role of MGMT in protection against the genotoxic effects of alkylating agents. Carcinogenesis 12, 1857–1867 (1991).

    CAS  PubMed  Article  Google Scholar 

  4. Kitange, G. J. et al. Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro Oncol. 11, 281–291 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Taylor, J. W. & Schiff, D. Treatment considerations for MGMT-unmethylated glioblastoma. Curr. Neurol. Neurosci. Rep. 15, 507 (2015).

    PubMed  Article  CAS  Google Scholar 

  6. Li, Q. J., Cai, J. Q. & Liu, C. Y. Evolving molecular genetics of glioblastoma. Chin. Med J. 129, 464–471 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Chen, X. et al. A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nat. Commun. 9, 2949 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. Lapointe, S., Perry, A. & Butowski, N. A. Primary brain tumours in adults. Lancet 392, 432–446 (2018).

    PubMed  Article  Google Scholar 

  9. Xiao, H. H. et al. Recent progress in polymer-based platinum drug delivery systems. Prog. Polym. Sci. 87, 70–106 (2018).

    CAS  Article  Google Scholar 

  10. Wang, S., Higgins, V. J., Aldrich-Wright, J. R. & Wu, M. J. Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator. J. Chem. Biol. 5, 51–61 (2012).

    CAS  PubMed  Article  Google Scholar 

  11. Graham, J., Mushin, M. & Kirkpatrick, P. Oxaliplatin. Nat. Rev. Drug Discov. 3, 11–12 (2004).

    CAS  PubMed  Article  Google Scholar 

  12. Pasetto, L. M., D’Andrea, M. R., Rossi, E. & Monfardini, S. Oxaliplatin-related neurotoxicity: how and why? Crit. Rev. Oncol. Hematol. 59, 159–168 (2006).

    PubMed  Article  Google Scholar 

  13. Golomb, L., Volarevic, S. & Oren, M. p53 and ribosome biogenesis stress: the essentials. FEBS Lett. 588, 2571–2579 (2014).

    CAS  PubMed  Article  Google Scholar 

  14. Bruno, P. M. et al. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat. Med 23, 461–471 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Pisani, M. J., Wheate, N. J., Keene, F. R., Aldrich-Wright, J. R. & Collins, J. G. Anionic PAMAM dendrimers as drug delivery vehicles for transition metal-based anticancer drugs. J. Inorg. Biochem 103, 373–380 (2009).

    CAS  PubMed  Article  Google Scholar 

  16. Wheate, N. J. et al. Novel platinum(ii)-based anticancer complexes and molecular hosts as their drug delivery vehicles. Dalton Trans. 2007, 5055–5064 (2007).

    Article  CAS  Google Scholar 

  17. Di Francia, R. et al. Current strategies to minimize toxicity of oxaliplatin: selection of pharmacogenomic panel tests. Anticancer Drugs 24, 1069–1078 (2013).

    PubMed  Article  CAS  Google Scholar 

  18. Jiang, Y. et al. SOD1 nanozyme with reduced toxicity and MPS accumulation. J. Control. Release 231, 38–49 (2016).

    CAS  PubMed  Article  Google Scholar 

  19. Jiang, Y., Brynskikh, A. M., Manickam, D. S. M. & Kabanov, A. V. SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature. J. Control. Release 213, 36–44 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Natarajan, G. et al. Nanoformulated copper/zinc superoxide dismutase exerts differential effects on glucose vs lipid homeostasis depending on the diet composition possibly via altered AMPK signaling. Transl. Res. 188, 10–26 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Caster, J. M., Patel, A. N., Zhang, T. & Wang, A. Investigational nanomedicines in 2016: a review of nanotherapeutics currently undergoing clinical trials. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 9, 1416 (2017).

    Article  Google Scholar 

  22. Liechty, W. B., Kryscio, D. R., Slaughter, B. V. & Peppas, N. A. Polymers for drug delivery systems. Annu Rev. Chem. Biomol. 1, 149–173 (2010).

    CAS  Article  Google Scholar 

  23. Meng, F. H., Hennink, W. E. & Zhong, Z. Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials 30, 2180–2198 (2009).

    CAS  PubMed  Article  Google Scholar 

  24. Guo, X. et al. Advances in redox-responsive drug delivery systems of tumor microenvironment. J. Nanobiotechnology 16, 74 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. Jiang, Y. et al. A ‘top-down’ approach to actuate poly(amine-co-ester) terpolymers for potent and safe mRNA delivery. Biomaterials 176, 122–130 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Kauffman, A. C. et al. Tunability of biodegradable poly(amine-co-ester) polymers for customized nucleic acid delivery and other biomedical applications. Biomacromolecules 19, 3861–3873 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Kuppusamy, P. et al. Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res. 62, 307–312 (2002).

    CAS  PubMed  Google Scholar 

  28. Zhu, Z. et al. Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis. J. Neurochem. 144, 93–104 (2018).

    CAS  PubMed  Article  Google Scholar 

  29. Efremenko, E. N. et al. A simple and highly effective catalytic nanozyme scavenger for organophosphorus neurotoxins. J. Control. Release 247, 175–181 (2017).

    CAS  PubMed  Article  Google Scholar 

  30. Harris, N. M. et al. Nano-particle delivery of brain derived neurotrophic factor after focal cerebral ischemia reduces tissue injury and enhances behavioral recovery. Pharm. Biochem. Behav. 150–151, 48–56 (2016).

    Article  CAS  Google Scholar 

  31. Jiang, Y. et al. Nanoformulation of brain-derived neurotrophic factor with target receptor-triggered-release in the central nervous system. Adv. Funct. Mater. 28, 1703982 (2018).

    PubMed  Article  CAS  Google Scholar 

  32. Jahangiri, A. et al. Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies. J. Neurosurg. 126, 191–200 (2017).

    PubMed  Article  Google Scholar 

  33. Bobo, R. H. et al. Convection-enhanced delivery of macromolecules in the brain. Proc. Natl Acad. Sci. USA 91, 2076–2080 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Fung, L. K. et al. Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 58, 672–684 (1998).

    CAS  PubMed  Google Scholar 

  35. Kataoka, K., Harada, A. & Nagasaki, Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Deliv. Rev. 47, 113–131 (2001).

    CAS  PubMed  Article  Google Scholar 

  36. Goodwin, A. P., Mynar, J. L., Ma, Y., Fleming, G. R. & Frechet, J. M. Synthetic micelle sensitive to IR light via a two-photon process. J. Am. Chem. Soc. 127, 9952–9953 (2005).

    CAS  PubMed  Article  Google Scholar 

  37. Su, H. et al. The role of critical micellization concentration in efficacy and toxicity of supramolecular polymers. Proc. Natl Acad. Sci. USA 117, 4518–4526 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Shang, L., Nienhaus, K. & Nienhaus, G. U. Engineered nanoparticles interacting with cells: size matters. J. Nanobiotechnology 12, 5 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. Prabha, S., Arya, G., Chandra, R., Ahmed, B. & Nimesh, S. Effect of size on biological properties of nanoparticles employed in gene delivery. Artif. Cells Nanomed. Biotechnol. 44, 83–91 (2016).

    CAS  PubMed  Article  Google Scholar 

  40. He, C., Hu, Y., Yin, L., Tang, C. & Yin, C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31, 3657–3666 (2010).

    CAS  PubMed  Article  Google Scholar 

  41. Mandl, H. K. et al. Optimizing biodegradable nanoparticle size for tissue-specific delivery. J. Control. Release 314, 92–101 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R. & Turner, N. D. Glutathione metabolism and its implications for health. J. Nutr. 134, 489–492 (2004).

    CAS  PubMed  Article  Google Scholar 

  43. Griffith, O. W. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic. Biol. Med 27, 922–935 (1999).

    CAS  PubMed  Article  Google Scholar 

  44. Meister, A. Glutathione metabolism and its selective modification. J. Biol. Chem. 263, 17205–17208 (1988).

    CAS  PubMed  Article  Google Scholar 

  45. Jones, D. P. et al. Glutathione measurement in human plasma. Evaluation of sample collection, storage and derivatization conditions for analysis of dansyl derivatives by HPLC. Clin. Chim. Acta 275, 175–184 (1998).

    CAS  PubMed  Article  Google Scholar 

  46. Snipstad, S. et al. Contact-mediated intracellular delivery of hydrophobic drugs from polymeric nanoparticles. Cancer Nanotechnol. 5, 8 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. Korst, A. E., Boven, E., van der Sterre, M. L., Fichtinger-Schepman, A. M. & van der Vijgh, W. J. Influence of single and multiple doses of amifostine on the efficacy and the pharmacokinetics of carboplatin in mice. Br. J. Cancer 75, 1439–1446 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Paraskar, A., Soni, S., Roy, B., Papa, A. L. & Sengupta, S. Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy. Nanotechnology 23, 075103 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Haragsim, L. & Zima, T. Protective effects of verapamil on cis-platinum and carboplatinum nephrotoxicity in dehydrated and normohydrated rats. Biochem. Int. 28, 273–276 (1992).

    CAS  PubMed  Google Scholar 

  50. Suttie, A. W. Histopathology of the spleen. Toxicol. Pathol. 34, 466–503 (2006).

    PubMed  Article  Google Scholar 

  51. Gupta, N., Lal, P., Vindal, A., Hadke, N. S. & Khurana, N. Spontaneous rupture of malarial spleen presenting as hemoperitoneum: a case report. J. Vector Borne Dis. 47, 119–120 (2010).

    PubMed  Google Scholar 

  52. Toxicology and Carcinogenesis Studies of 3,3′,4,4′-Tetrachloroazobenzene (TCAB) (CAS No. 14047-09-7) in Harlan Sprague-Dawley Rats and B6C3F1 Mice (Gavage Studies) Techincal Report Series (National Toxicology Program, 2010).

  53. Toxicology and Carcinogenesis Studies of α,β-Thujone (CAS No. 76231-76-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series (National Toxicology Program, 2011).

  54. Ward, J. M., Rehg, J. E. & Morse, H. C. 3rd Differentiation of rodent immune and hematopoietic system reactive lesions from neoplasias. Toxicol. Pathol. 40, 425–434 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  55. Andreassen, P. R. & Ren, K. Fanconi anemia proteins, DNA interstrand crosslink repair pathways, and cancer therapy. Curr. Cancer Drug Targets 9, 101–117 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Thambi, T. et al. Bioreducible carboxymethyl dextran nanoparticles for tumor-targeted drug delivery. Adv. Health. Mater. 3, 1829–1838 (2014).

    CAS  Article  Google Scholar 

  57. Son, S. et al. Anti-Trop2 antibody-conjugated bioreducible nanoparticles for targeted triple negative breast cancer therapy. Int J. Biol. Macromol. 110, 406–415 (2018).

    CAS  PubMed  Article  Google Scholar 

  58. Xia, W. et al. Bioreducible polyethylenimine-delivered siRNA targeting human telomerase reverse transcriptase inhibits HepG2 cell growth in vitro and in vivo. J. Control. Release 157, 427–436 (2012).

    CAS  PubMed  Article  Google Scholar 

  59. Florinas, S., Kim, J., Nam, K., Janat-Amsbury, M. M. & Kim, S. W. Ultrasound-assisted siRNA delivery via arginine-grafted bioreducible polymer and microbubbles targeting VEGF for ovarian cancer treatment. J. Control. Release 183, 1–8 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Lopez-Bertoni, H. et al. Bioreducible polymeric nanoparticles containing multiplexed cancer stem cell regulating miRNAs inhibit glioblastoma growth and prolong survival. Nano Lett. 18, 4086–4094 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Carlson, B. L., Pokorny, J. L., Schroeder, M. A. & Sarkaria, J. N. Establishment, maintenance and in vitro and in vivo applications of primary human glioblastoma multiforme (GBM) xenograft models for translational biology studies and drug discovery. Curr. Protoc. Pharmacol. https://doi.org/10.1002/0471141755.ph1416s52 (2011).

  62. Vaubel, R. A. et al. Genomic and phenotypic characterization of a broad panel of patient-derived xenografts reflects the diversity of glioblastoma. Clin. Cancer Res. 26, 1094–1104 (2020).

    CAS  PubMed  Article  Google Scholar 

  63. Tew, B. Y. et al. Patient-derived xenografts of central nervous system metastasis reveal expansion of aggressive minor clones. Neuro Oncol. 22, 70–83 (2020).

    CAS  PubMed  Article  Google Scholar 

  64. Randall, E. C. et al. Localized metabolomic gradients in patient-derived xenograft models of glioblastoma. Cancer Res. 80, 1258–1267 (2020).

    CAS  PubMed  Article  Google Scholar 

  65. Randall, E. C. et al. Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma. Nat. Commun. 9, 4904 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. Schenone, M., Dancik, V., Wagner, B. K. & Clemons, P. A. Target identification and mechanism of action in chemical biology and drug discovery. Nat. Chem. Biol. 9, 232–240 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Reichel, D. et al. Near infrared fluorescent nanoplatform for targeted intraoperative resection and chemotherapeutic treatment of glioblastoma. ACS Nano 14, 8392–8408 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Moser, V. C. Functional assays for neurotoxicity testing. Toxicol. Pathol. 39, 36–45 (2011).

    PubMed  Article  Google Scholar 

  69. Wu, T. et al. A nanobody-conjugated DNA nanoplatform for targeted platinum-drug delivery. Angew. Chem. Int. Ed. 58, 14224–14228 (2019).

    CAS  Article  Google Scholar 

  70. Song, E. et al. Surface chemistry governs cellular tropism of nanoparticles in the brain. Nat. Commun. 8, 15322 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Serwer, L., Hashizume, R., Ozawa, T. & James, C. D. Systemic and local drug delivery for treating diseases of the central nervous system in rodent models. J. Vis. Exp. 42, 1992 (2010).

    Google Scholar 

  72. Xia, J. & Wishart, D. S. Web-based inference of biological patterns, functions and pathways from metabolomic data using MetaboAnalyst. Nat. Protoc. 6, 743–760 (2011).

    CAS  PubMed  Article  Google Scholar 

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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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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.

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Correspondence to Haihua Xiao or W. Mark Saltzman.

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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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