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Gold nanoparticle-assisted delivery of brain-derived neurotrophic factor to cerebral organoids

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Abstract

Gold nanoparticle (AuNP)-assisted delivery of proteins/drugs to cells or in vivo systems has long been studied. However, their interaction with in vivo mimicking organoids is still largely unknown. Here, we conjugated brain-derived neurotropic factor (BDNF) to the AuNP surface and monitored how AuNP-BDNF interacts with cerebral organoids. Data suggest that AuNP-BDNF can successfully enter cerebral organoids and can be found up to 15.21 µm inside cerebral organoids. AuNP-BDNF does not induce significant cytotoxicity to cerebral organoids at concentrations up to 2 nM and increases the expression of 75 genes compared to control cerebral organoids. These data suggest the successful delivery of BDNF through AuNP-BDNF conjugation in cerebral organoids, and the conjugation can affect its differentiation.

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References

  1. Liu, J. Y.; Peng, Q. Protein-gold nanoparticle interactions and their possible impact on biomedical applications. Acta Biomater. 2017, 55, 13–27.

    Article  CAS  Google Scholar 

  2. Rana, S.; Bajaj, A.; Mout, R.; Rotello, V. M. Monolayer coated gold nanoparticles for delivery applications. Adv. Drug Deliv. Rev. 2012, 64, 200–216.

    Article  CAS  Google Scholar 

  3. Jeong, E. H.; Jung, G.; Hong, C. A.; Lee, H. Gold nanoparticle (AuNP)-based drug delivery and molecular imaging for biomedical applications. Arch. Pharm. Res. 2014, 37, 53–59.

    Article  CAS  Google Scholar 

  4. Almeida, J. P. M.; Lin, A. Y.; Figueroa, E. R.; Foster, A. E.; Drezek, R. A. In vivo gold nanoparticle delivery of peptide vaccine induces anti-tumor immune response in prophylactic and therapeutic tumor models. Small 2015, 11, 1453–1459.

    Article  CAS  Google Scholar 

  5. Kim, C. K.; Ghosh, P.; Rotello, V. M. Multimodal drug delivery using gold nanoparticles. Nanoscale 2009, 1, 61–67.

    Article  CAS  Google Scholar 

  6. Ryou, S. M.; Yeom, J. H.; Kang, H. J.; Won, M.; Kim, J. S.; Lee, B.; Seong, M. J.; Ha, N. C.; Bae, J.; Lee, K. Gold nanoparticle-DNA aptamer composites as a universal carrier for in vivo delivery of biologically functional proteins. J. Control. Release 2014, 196, 287–294.

    Article  CAS  Google Scholar 

  7. Lee, C. S.; Kim, H.; Yu, J.; Yu, S. H.; Ban, S.; Oh, S.; Jeong, D.; Im, J.; Baek, M. J.; Kim, T. H. Doxorubicin-loaded oligonucleotide conjugated gold nanoparticles: A promising in vivo drug delivery system for colorectal cancer therapy. Eur. J. Med. Chem. 2017, 142, 416–423.

    Article  CAS  Google Scholar 

  8. Mbatha, L. S.; Maiyo, F.; Daniels, A.; Singh, M. Dendrimer-coated gold nanoparticles for efficient folate-targeted mRNA delivery in vitro. Pharmaceutics 2021, 13, 900.

    Article  CAS  Google Scholar 

  9. Lancaster, M. A.; Renner, M.; Martin, C. A.; Wenzel, D.; Bicknell, L. S.; Hurles, M. E.; Homfray, T.; Penninger, J. M.; Jackson, A. P.; Knoblich, J. A. Cerebral organoids model human brain development and microcephaly. Nature 2013, 501, 373–379.

    Article  CAS  Google Scholar 

  10. Lancaster, M. A.; Corsini, N. S.; Wolfinger, S.; Gustafson, E. H.; Phillips, A. W.; Burkard, T. R.; Otani, T.; Livesey, F. J.; Knoblich, J. A. Guided self-organization and cortical plate formation in human brain organoids. Nat. Biotechnol. 2017, 35, 659–666.

    Article  CAS  Google Scholar 

  11. Xiang, Y. F.; Tanaka, Y.; Patterson, B.; Kang, Y. J.; Govindaiah, G.; Roselaar, N.; Cakir, B.; Kim, K. Y.; Lombroso, A. P.; Hwang, S. M. et al. Fusion of regionally specified HPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell 2017, 21, 383–398.e7.

    Article  CAS  Google Scholar 

  12. Amin, N. D.; Paşca, S. P. Building models of brain disorders with three-dimensional organoids. Neuron 2018, 100, 389–405.

    Article  CAS  Google Scholar 

  13. Koo, B.; Choi, B.; Park, H.; Yoon, K. J. Past, present, and future of brain organoid technology. Mol. Cells 2019, 42, 617–627.

    CAS  Google Scholar 

  14. Mansour, A. A.; Gonçalves, J. T.; Bloyd, C. W.; Li, H.; Fernandes, S.; Quang, D.; Johnston, S.; Parylak, S. L.; Jin, X.; Gage, F. H. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 2018, 36, 432–441.

    Article  CAS  Google Scholar 

  15. Hodge, R. D.; Bakken, T. E.; Miller, J. A.; Smith, K. A.; Barkan, E. R.; Graybuck, L. T.; Close, J. L.; Long, B.; Johansen, N.; Penn, O. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature 2019, 573, 61–68.

    Article  CAS  Google Scholar 

  16. Pryluk, R.; Kfir, Y.; Gelbard-Sagiv, H.; Fried, I.; Paz, R. A tradeoff in the neural code across regions and species. Cell 2019, 176, 597–609.E18.

    Article  CAS  Google Scholar 

  17. Gordon, A.; Yoon, S. J.; Tran, S. S.; Makinson, C. D.; Park, J. Y.; Andersen, J.; Valencia, A. M.; Horvath, S.; Xiao, X. S.; Huguenard, J. R. et al. Long-term maturation of human cortical organoids matches key early postnatal transitions. Nat. Neurosci. 2021, 24, 331–342.

    Article  CAS  Google Scholar 

  18. Kim, H. M.; Lee, S. H.; Lim, J.; Yoo, J.; Hwang, D. Y. The epidermal growth factor receptor variant type III mutation frequently found in gliomas induces astrogenesis in human cerebral organoids. Cell Prolif. 2021, 54, e12965.

    CAS  Google Scholar 

  19. Groveman, B. R.; Ferreira, N. C.; Foliaki, S. T.; Walters, R. O.; Winkler, C. W.; Race, B.; Hughson, A. G.; Zanusso, G.; Haigh, C. L. Human cerebral organoids as a therapeutic drug screening model for creutzfeldt-jakob disease. Sci. Rep. 2021, 11, 5165.

    Article  CAS  Google Scholar 

  20. Arzua, T.; Yan, Y. S.; Jiang, C. S.; Logan, S.; Allison, R. L.; Wells, C.; Kumar, S. N.; Schäfer, R.; Bai, X. W. Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids. Transl. Psychiatry 2020, 10, 347.

    Article  CAS  Google Scholar 

  21. Farooq, M. U.; Novosad, V.; Rozhkova, E. A.; Wali, H.; Ali, A.; Fateh, A. A.; Neogi, P. B.; Neogi, A.; Wang, Z. M. Gold nanoparticles-enabled efficient dual delivery of anticancer therapeutics to HeLa cells. Sci. Rep. 2018, 8, 2907.

    Article  Google Scholar 

  22. Li, W.; Cao, Z. W.; Liu, R.; Liu, L. L.; Li, H.; Li, X.; Chen, Y. W.; Lu, C.; Liu, Y. Y. AuNPs as an important inorganic nanoparticle applied in drug carrier systems. Artif. Cells Nanomed. Biotechnol. 2019, 47, 4222–4233.

    Article  CAS  Google Scholar 

  23. Cho, K.; Wang, X.; Nie, S. M.; Chen, Z.; Shin, D. M. Therapeutic nanoparticles for drug delivery in cancer. Clin. Cancer Res. 2008, 14, 1310–1316.

    Article  CAS  Google Scholar 

  24. Amina, S. J.; Guo, B. A review on the synthesis and functionalization of gold nanoparticles as a drug delivery vehicle. Int. J. Nanomedicine 2020, 15, 9823–9857.

    Article  CAS  Google Scholar 

  25. Jazayeri, M. H.; Amani, H.; Pourfatollah, A. A.; Pazoki-Toroudi, H.; Sedighimoghaddam, B. Various methods of gold nanoparticles (GNPs) conjugation to antibodies. Sens. Bio-Sens. Res. 2016, 9, 17–22.

    Article  Google Scholar 

  26. Doane, T.; Burda, C. Nanoparticle mediated non-covalent drug delivery. Adv. Drug Deliv. Rev. 2013, 65, 607–621.

    Article  CAS  Google Scholar 

  27. Sun, N.; Meng, X. Q.; Liu, Y. X.; Song, D.; Jiang, C. L.; Cai, J. Q. Applications of brain organoids in neurodevelopment and neurological diseases. J. Biomed. Sci. 2021, 28, 30.

    Article  Google Scholar 

  28. Yakoub, A. M. Cerebral organoids exhibit mature neurons and astrocytes and recapitulate electrophysiological activity of the human brain. Neural Regen Res 2019, 14, 757–761.

    Article  Google Scholar 

  29. Eremeev, A. V.; Lebedeva, O. S.; Bogomiakova, M. E.; Lagarkova, M. A.; Bogomazova, A. N. Cerebral organoids-challenges to establish a brain prototype. Cells 2021, 10, 1790.

    Article  CAS  Google Scholar 

  30. Bath, K. G.; Akins, M. R.; Lee, F. S. BDNF control of adult SVZ neurogenesis. Dev. Psychobiol. 2012, 54, 578–589.

    Article  CAS  Google Scholar 

  31. Schäbitz, W. R.; Steigleder, T.; Cooper-Kuhn, C. M.; Schwab, S.; Sommer, C.; Schneider, A.; Kuhn, H. G. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 2007, 38, 2165–2172.

    Article  Google Scholar 

  32. Sotnikov, D. V.; Berlina, A. N.; Ivanov, V. S.; Zherdev, A. V.; Dzantiev, B. B. Adsorption of proteins on gold nanoparticles: One or more layers? Colloids Surf. B Biointerfaces 2019, 173, 557–563.

    Article  CAS  Google Scholar 

  33. Paşca, A. M.; Sloan, S. A.; Clarke, L. E.; Tian, Y.; Makinson, C. D.; Huber, N.; Kim, C. H.; Park, J. Y.; O’Rourke, N. A.; Nguyen, K. D. et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 2015, 12, 671–678.

    Article  Google Scholar 

  34. nanoComposix. Interpreting Particle Spectra During Protein Conjugation [Online]. https://nanocomposix.com/pages/interpreting-particle-spectra-during-protein-conjugation (accessed Jul 27, 2021).

  35. Arcila-Lozano, L. S.; Ríos-Corripio, M. A.; García-Pérez, B. E.; Jaramillo-Flores, M. E.; González, C. A.; Rocha-Gracia, R. C.; Gracia-Jiménez, J. M.; Rojas-López, M. Fluorescent bioconjugate based on gold nanoparticles for the determination of Staphylococcus aureus. Anal. Lett. 2017, 50, 1150–1167.

    Article  CAS  Google Scholar 

  36. Hempstead, B. L. Brain-derived neurotrophic factor: Three ligands, many actions. Trans. Am. Clin. Climatol. Assoc. 2015, 126, 9–19.

    Google Scholar 

  37. Lee, E.; Jeon, H.; Lee, M.; Ryu, J.; Kang, C.; Kim, S.; Jung, J.; Kwon, Y. Molecular origin of AuNPs-induced cytotoxicity and mechanistic study. Sci. Rep. 2019, 9, 2494.

    Article  Google Scholar 

  38. Lancaster, M. A.; Knoblich, J. A. Generation of cerebral organoids from human pluripotent stem cells. Nat. Protoc. 2014, 9, 2329–2340.

    Article  CAS  Google Scholar 

  39. Huang, E. J.; Reichardt, L. F. Neurotrophins: Roles in neuronal development and function. Annu. Rev. Neurosci. 2001, 24, 677–736.

    Article  CAS  Google Scholar 

  40. Ferreira, F. F.; Ribeiro, F. F.; Rodrigues, R. S.; Sebastião, A. M.; Xapelli, S. Brain-derived neurotrophic factor (BDNF) role in cannabinoid-mediated neurogenesis. Front. Cell Neurosci. 2018, 12, 441.

    Article  CAS  Google Scholar 

  41. Qian, X. Y.; Jacob, F.; Song, M. M.; Nguyen, H. N.; Song, H. J.; Ming, G. L. Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat. Protoc. 2018, 13, 565–580.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors greatly acknowledge the financial support from the Ministry of Science and ICT (No. 2021R1A2C2011195) and the Korea Research Institute of Chemical Technology of Republic of Korea (Nos. SI2131-50 and SI2152-20).

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  1. Sung Bum Park and Hye-Jin Cho contributed equally to this work.

Authors and Affiliations

  1. Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea

    Sung Bum Park, Sang Rin Moon, Kyoung Jin Choi, Won Hoon Jung, Ki Young Kim & Byumseok Koh

  2. Chemical Platform Technology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea

    Hye-Jin Cho

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  1. Sung Bum Park
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Correspondence to Ki Young Kim or Byumseok Koh.

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Park, S.B., Cho, HJ., Moon, S.R. et al. Gold nanoparticle-assisted delivery of brain-derived neurotrophic factor to cerebral organoids. Nano Res. 15, 3099–3105 (2022). https://doi.org/10.1007/s12274-021-3975-x

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