Chenyang Xiang, Yuxuan Zhang, Weisheng Guo, Xing-Jie Liang. Biomimetic carbon nanotubes for neurological disease therapeutics as inherent medication[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 239-248

Biomimetic carbon nanotubes for neurological disease therapeutics as inherent medication
Chenyang Xianga, Yuxuan Zhangb, Weisheng Guoa, Xing-Jie Lianga,b
a Translational Medicine Center, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China;
b CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
Nowadays, nanotechnology is revolutionizing the approaches to different fields from manufacture to health. Carbon nanotubes (CNTs) as promising candidates in nanomedicine have great potentials in developing novel entities for central nervous system pathologies, due to their excellent physicochemical properties and ability to interface with neurons and neuronal circuits. However, most of the studies mainly focused on the drug delivery and bioimaging applications of CNTs, while neglect their application prospects as therapeutic drugs themselves. At present, the relevant reviews are not available yet. Herein we summarized the latest advances on the biomedical and therapeutic applications of CNTs in vitro and in vivo for neurological diseases treatments as inherent therapeutic drugs. The biological mechanisms of CNTs-mediated bio-medical effects and potential toxicity of CNTs were also intensely discussed. It is expected that CNTs will exploit further neurological applications on disease therapy in the near future.
Key words:    Carbon nanotubes    Nervous system diseases    Drug delivery    Therapeutic drug    Inherent medication    Toxicity   
Received: 2019-04-30     Revised: 2019-08-26
DOI: 10.1016/j.apsb.2019.11.003
Funds: This work was supported by the National Natural Science Foundation of China (31971302, 31430031, 81601603).
Corresponding author: Weisheng Guo, Xing-Jie Liang;
Author description:
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Chenyang Xiang
Yuxuan Zhang
Weisheng Guo
Xing-Jie Liang

1. Iijima S. Helical microtubules of graphitic carbon. Nature 1991;354:56-8.
2. Saito N, Usui Y, Aoki K, Narita N, Shimizu M, Hara K, et al. Carbon nanotubes:biomaterial applications. Chem Soc Rev 2009;38:1897-903.
3. Dimiev AM, Khannanov A, Vakhitov I, Kiiamov A, Shukhina K, Tour JM. Revisiting the mechanism of oxidative unzipping of multiwall carbon nanotubes to graphene nanoribbons. ACS Nano 2018;12:3985-93.
4. Chen Z, Wu R, Liu Y, Ha Y, Guo Y, Sun D, et al. Ultrafine co nanoparticles encapsulated in carbon-nanotubes-grafted graphene sheets as advanced electrocatalysts for the hydrogen evolution reaction. Adv Mater 2018;30:1802011.
5. Fang R, Chen K, Yin L, Sun Z, Li F, Cheng HM. The Regulating role of carbon nanotubes and graphene in lithium-ion and lithium-sulfur batteries. Adv Mater 2019;31:1800863.
6. Wang X, Lee JH, Li R, Liao YP, Kang J, Chang CH, et al. Toxicological profiling of highly purified single-walled carbon nanotubes with different lengths in the rodent lung and Escherichia coli. Small 2018;14:1703915.
7. Sahoo AK, Kanchi S, Mandal T, Dasgupta C, Maiti PK. Translocation of bioactive molecules through carbon nanotubes embedded in the lipid membrane. ACS Appl Mater Inter 2018;10:6168-79.
8. Huth K, Glaeske M, Achazi K, Gordeev G, Kumar S, Arenal R, et al. Fluorescent polymer-single-walled carbon nanotube complexes with charged and noncharged dendronized perylene bisimides for bioimaging studies. Small 2018;14:1800796.
9. Battigelli A, Menard-Moyon C, Da Ros T, Prato M, Bianco A. Endowing carbon nanotubes with biological and biomedical properties by chemical modifications. Adv Drug Deliv Rev 2013;65:1899-920.
10. Hong EJ, Choi DG, Shim MS. Targeted and effective photodynamic therapy for cancer using functionalized nanomaterials. Acta Pharm Sin B 2016;6:297-307.
11. Gaillard C, Duval M, Dumortier H, Bianco A. Carbon nanotubecoupled cell adhesion peptides are non-immunogenic:a promising step toward new biomedical devices. J Pept Sci 2011;17:139-42.
12. Medepalli K, Alphenaar B, Raj A, Sethu P. Evaluation of the direct and indirect response of blood leukocytes to carbon nanotubes (CNTs). Nanomed Nanotechnol 2011;7:983-91.
13. Liu Z, Chen K, Davis C, Sherlock S, Cao Q, Chen X, et al. Drug delivery with carbon nanotubes for in vivo cancer treatment. Cancer Res 2008;68:6652-60.
14. Qiao Y, Li CM, Bao SJ, Bao QL. Carbon nanotube/polyaniline composite as anode material for microbial fuel cells. J Power Sources 2007;170:79-84.
15. Kinloch IA, Suhr J, Lou J, Young RJ, Ajayan PM. Composites with carbon nanotubes and graphene:an outlook. Science 2018;362:547-53.
16. Sgobba V, Guldi DM. Carbon nanotubes-electronic/electrochemical properties and application for nanoelectronics and photonics. Chem Soc Rev 2009;38:165-84.
17. Li Y, Wei Q, Ma F, Li X, Liu F, Zhou M. Surface-enhanced Raman nanoparticles for tumor theranostics applications. Acta Pharm Sin B 2018;8:349-59.
18. Yang Y, Zhang J, Zhuang J, Wang X. Synthesis of nitrogen-doped carbon nanostructures from polyurethane sponge for bioimaging and catalysis. Nanoscale 2015;7:12284-90.
19. Zhao J, Chen J, Ma S, Liu Q, Huang L, Chen X, et al. Recent developments in multimodality fluorescence imaging probes. Acta Pharm Sin B 2018;8:320-38.
20. Liu J, Wang C, Wang X, Wang X, Cheng L, Li Y, et al. Mesoporous silica coated single-walled carbon nanotubes as a multifunctional light-responsive platform for cancer combination therapy. Adv Func Mater 2015;25:384-92.
21. Newland B, Taplan C, Pette D, Friedrichs J, Steinhart M, Wang W, et al. Soft and flexible poly(ethylene glycol) nanotubes for local drug delivery. Nanoscale 2018;10:8413-21.
22. Monaco AM, Giugliano M. Carbon-based smart nanomaterials in biomedicine and neuroengineering. Beilstein J Nanotechnol 2014;5:1849-63.
23. Malarkey EB, Fisher KA, Bekyarova E, Liu W, Haddon RC, Parpura V. Conductive single-walled carbon nanotube substrates modulate neuronal growth. Nano Lett 2009;9:264-8.
24. Hu H, Ni Y, Montana V, Haddon RC, Parpura V. Chemically functionalized carbon nanotubes as substrates for neuronal growth. Nano Lett 2004;4:507-11.
25. Mattson MP, Haddon RC, Rao AM. Molecular functionalization of carbon nanotubes and use as substrates for neuronal growth. J Mol Neurosci 2000;14:175-82.
26. Matsumoto K, Sato C, Naka Y, Kitazawa A, Whitby RL, Shimizu N. Neurite outgrowths of neurons with neurotrophin-coated carbon nanotubes. J Biosci Bioeng 2007;103:216-20.
27. Yu W, Jiang X, Cai M, Zhao W, Ye D, Zhou Y, Zhu C, et al. A novel electrospun nerve conduit enhanced by carbon nanotubes for peripheral nerve regeneration. Nanotechnology 2014;25:165102-15.
28. Kam NW, Jan E, Kotov NA. Electrical stimulation of neural stem cells mediated by humanized carbon nanotube composite made with extracellular matrix protein. Nano Lett 2009;9:273-8.
29. Shao H, Li T, Zhu R, Xu X, Yu J, Chen S, et al. Carbon nanotube multilayered nanocomposites as multifunctional substrates for actuating neuronal differentiation and functions of neural stem cells. Biomaterials 2018;175:93-109.
30. Park SY, Choi DS, Jin HJ, Park J, Byun KE, Lee KB, et al. Polarization-controlled differentiation of human neural stem cells using synergistic cues from the patterns of carbon nanotube monolayer coating. ACS Nano 2011;5:4704-11.
31. Li J, Cassell A, Delzeit L, Han J, Meyyappan M. Novel threedimensional electrodes:electrochemical properties of carbon nanotube ensembles. J Phys Chem B 2002;106:9299-305.
32. Wang K, Fishman HA, Dai H, Harris JS. Neural Stimulation with a carbon nanotube microelectrode array. Nano Lett 2006;6:2043-8.
33. Meng C, Liu C, Fan S. Flexible carbon nanotube/polyaniline paperlike films and their enhanced electrochemical properties. Electrochem Commun 2009;11:186-9.
34. Fernandes DM, Nunes M, Bachiller-Baeza B, Rodríguez-Ramos I, Guerrero-Ruiz A, Delerue-Matos C, et al. PMo11V@N-CNT electrochemical properties and its application as electrochemical sensor for determination of acetaminophen. J Solid State Electr 2017;21:1059-68.
35. Jan E, Hendricks JL, Husaini V, Richardson-Burns SM, Sereno A, Martin DC, et al. Layered carbon nanotube-polyelectrolyte electrodes outperform traditional neural interface materials. Nano Lett 2009;9:4012-8.
36. Lu Y, Li T, Zhao X, Li M, Cao Y, Yang H, et al. Electrodeposited polypyrrole/carbon nanotubes composite films electrodes for neural interfaces. Biomaterials 2010;31:5169-81.
37. Monteiro-Riviere NA, Nemanich RJ, Inman AO, Wang YY, Riviere JE. Multi-walled carbon nanotube interactions with human epidermal keratinocytes. Toxicol Lett 2005;155:377-84.
38. Wang L, Zhang L, Xue X, Ge G, Liang X. Enhanced dispersibility and cellular transmembrane capability of single-wall carbon nanotubes by polycyclic organic compounds as chaperon. Nanoscale 2012;4:3983-9.
39. Ma X, Zhang LH, Wang LR, Xue X, Sun JH, Wu Y, et al. Singlewalled carbon nanotubes alter cytochrome c electron transfer and modulate mitochondrial function. ACS Nano 2012;6:10486-96.
40. Wang LR, Xue X, Hu XM, Wei MY, Zhang CQ, Ge GL, et al. Structure-dependent mitochondrial dysfunction and hypoxia induced with single-walled carbon nanotubes. Small 2014;10:2859-69.
41. Malarkey EB, Reyes RC, Zhao B, Haddon RC, Parpura V. Water soluble single-walled carbon nanotubes inhibit stimulated endocytosis in neurons. Nano Lett 2008;8:3538-42.
42. Xue X, Wang LR, Sato Y, Jiang Y, Berg M, Yang DS, et al. Singlewalled carbon nanotubes alleviate autophagic/lysosomal defects in primary glia from a mouse model of Alzheimer's disease. Nano Lett 2014;14:5110-7.
43. Kateb B, van Handel M, Zhang L, Bronikowski MJ, Manohara H, Badie B. Internalization of MWCNTs by microglia:possible application in immunotherapy of brain tumors. Neuroimage 2007;37:9-17.
44. Zhao D, Alizadeh D, Zhang L, Liu W, Farrukh O, Manuel E, et al. Carbon nanotubes enhance CpG uptake and potentiate antiglioma immunity. Clin Cancer Res 2011;17:771-82.
45. VanHandel M, Alizadeh D, Zhang L, Kateb B, Bronikowski M, Manohara H, et al. Selective uptake of multi-walled carbon nanotubes by tumor macrophages in a murine glioma model. J Neuroimmunol 2009;208:3-9.
46. Ouyang M, White EE, Ren H, Guo Q, Zhang I, Gao H, et al. Metronomic doses of temozolomide enhance the efficacy of carbon nanotube CpG immunotherapy in an invasive glioma model. PLoS One 2016;11:0148139.
47. Stephenson J, Nutma E, van der Valk P, Amor S. Inflammation in CNS neurodegenerative diseases. Immunology 2018;154:204-19.
48. Ajetunmobi A, Prina-Mello A, Volkov Y, Corvin A, Tropea D. Nanotechnologies for the study of the central nervous system. Prog Neurobiol 2014;123:18-36.
49. Jucker M, Walker LC. Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nature Neurosci 2018;21:1341-9.
50. Thellung S, Scoti B, Corsaro A, Villa V, Nizzari M, Gagliani MC, et al. Pharmacological activation of autophagy favors the clearing of intracellular aggregates of misfolded prion protein peptide to prevent neuronal death. Cell Death Dis 2018;9:166-81.
51. Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, et al. Inflammation in neurodegenerative diseasesdan update. Immunology 2014;142:151-66.
52. Guerra F, Girolimetti G, Beli R, Mitruccio M, Pacelli C, Ferretta A, et al. Synergistic effect of mitochondrial and lysosomal dysfunction in Parkinson's disease. Cells 2019;8:452-77.
53. Giordano S, Darley-Usmar V, Zhang J. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol 2014;2:82-90.
54. Mitra J, Guerrero EN, Hegde PM, Liachko NF, Wang H, Vasquez V, et al. Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects. Proc Natl Acad Sci U S A 2019;116:4696-705.
55. Ramanan VK, Saykin AJ. Pathways to neurodegeneration:mechanistic insights from GWAS in Alzheimer's disease, Parkinson's disease, and related disorders. Am J Neurodegener Dis 2013;2:145-75.
56. Vanderweyde T, Youmans K, Liu-Yesucevitz L, Wolozin B. Role of stress granules and RNA-binding proteins in neurodegeneration:a mini-review. Gerontology 2013;59:524-33.
57. Maurel C, Dangoumau A, Marouillat S, Brulard C, Chami A, Hergesheimer R, et al. Causative genes in amyotrophic lateral sclerosis and protein degradation pathways:a link to neurodegeneration. Mol Neurobiol 2018;55:6480-99.
58. Cellot G, Cilia E, Cipollone S, Rancic V, Sucapane A, Giordani S, et al. Carbon nanotubes might improve neuronal performance by favouring electrical shortcuts. Nat Nanotechnol 2009;4:126-33.
59. Ahn HS, Hwang JY, Kim MS, Lee JY, Kim JW, Kim HS, et al. Carbon-nanotube-interfaced glass fiber scaffold for regeneration of transected sciatic nerve. Acta Biomater 2015;13:324-34.
60. Lee SJ, Zhu W, Nowicki M, Lee G, Dong Nyoung H, Kim J, et al. 3D printing nano conductive multi-walled carbon nanotube scaffolds for nerve regeneration. J Neural Eng 2018;15:016018.
61. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated definition of stroke for the 21st century:a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:2064-89.
62. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics-2012 update:a report from the American Heart Association. Circulation 2012;125:e2-220.
63. Lee HJ, Park J, Yoon OJ, Kim HW, Lee DY, Kim do H, et al. Aminemodified single-walled carbon nanotubes protect neurons from injury in a rat stroke model. Nat Nanotechnol 2011;6:121-5.
64. Moon SU, Kim J, Bokara KK, Kim JY, Khang D, Webster TJ, et al. Carbon nanotubes impregnated with subventricular zone neural progenitor cells promotes recovery from stroke. Int J Nanomed 2012;7:2751-65.
65. Minnikanti S, Pereira MG, Jaraiedi S, Jackson K, Costa-Neto CM, Li Q, et al. In vivo electrochemical characterization and inflammatory response of multiwalled carbon nanotube-based electrodes in rat hippocampus. J Neural Eng 2010;7:16002-13.
66. Waltzman SB. Cochlear implants:current status. Expert Rev Med Devices 2006;3:647-55.
67. Johnston JC, Durieux-Smith A, Angus D, O'Connor A, Fitzpatrick E. Bilateral paediatric cochlear implants:a critical review. Int J Audiol 2009;48:601-17.
68. Bareket L, Waiskopf N, Rand D, Lubin G, David-Pur M, Ben-Dov J, et al. Semiconductor nanorod-carbon nanotube biomimetic films for wire-free photostimulation of blind retinas. Nano Lett 2014;14:6685-92.
69. Xue X, Yang JY, He Y, Wang LR, Liu P, Yu LS, et al. Aggregated single-walled carbon nanotubes attenuate the behavioural and neurochemical effects of methamphetamine in mice. Nat Nanotechnol 2016; 11:613-20.
70. Zhang X, Yin J, Peng C, Hu W, Zhu Z, Li W, et al. Distribution and biocompatibility studies of graphene oxide in mice after intravenous administration. Carbon 2011;49:986-95.
71. Huang H, Liu M, Jiang R, Chen J, Mao L, Wen Y, et al. Facile modification of nanodiamonds with hyperbranched polymers based on supramolecular chemistry and their potential for drug delivery. J Colloid Interf Sci 2018;513:198-204.
72. Jiang R, Liu M, Huang H, Mao L, Huang Q, Wen Y, et al. Facile fabrication of organic dyed polymer nanoparticles with aggregationinduced emission using an ultrasound-assisted multicomponent reaction and their biological imaging. J Colloid Interf Sci 2018;519:137-44.
73. Zhang X, Wang K, Liu M, Zhang X, Tao L, Chen Y, et al. Polymeric AIE-based nanoprobes for biomedical applications:recent advances and perspectives. Nanoscale 2015;7:11486-508.
74. Zhang X, Wang S, Xu L, Feng L, Ji Y, Tao L, et al. Biocompatible polydopamine fluorescent organic nanoparticles:facile preparation and cell imaging. Nanoscale 2012;4:5581-4.
75. Zhang X, Zhang X, Yang B, Liu M, Liu W, Chen Y, et al. Fabrication of aggregation induced emission dye-based fluorescent organic nanoparticles via emulsion polymerization and their cell imaging applications. Polym Chem 2014;5:399-404.
76. Liu J, Lam JWY, Tang BZ. Acetylenic polymers:syntheses, structures, and functions. Chem Rev UK 2009;109:5799-867.
77. Zhang X, Hu W, Li J, Tao L, Wei Y. A comparative study of cellular uptake and cytotoxicity of multi-walled carbon nanotubes, graphene oxide, and nanodiamond. Toxicol Res UK 2012;1:62-8.
78. Yuan J, Gao H, Ching CB. Comparative protein profile of human hepatoma HepG2 cells treated with graphene and single-walled carbon nanotubes:an iTRAQ-coupled 2D LCeMS/MS proteome analysis. Toxicol Lett 2011;207:213-21.
79. Liu Z, Cai W, He L, Nakayama N, Chen K, Sun X, et al. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat Nanotechnol 2007;2:47-52.
80. Wang H, Wang J, Deng X, Sun H, Shi Z, Gu Z, et al. Biodistribution of carbon single-wall carbon nanotubes in mice. Journal Nanosc Nanotechnol 2004;4:1019-24.
81. Singh R, Pantarotto D, Lacerda L, Pastorin G, Klumpp C, Prato M, et al. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc Natl Acad Sci U S A 2006;103:3357-62.
82. Alidori S, Thorek DLJ, Beattie BJ, Ulmert D, Almeida BA, Monette S, et al. Carbon nanotubes exhibit fibrillar pharmacology in primates. PLoS One 2017;12:0183902.
83. Kafa H, Wang JT, Rubio N, Venner K, Anderson G, Pach E, et al. The interaction of carbon nanotubes with an in vitro bloodebrain barrier model and mouse brain in vivo. Biomaterials 2015;53:437-52.
84. Nunes A, Bussy C, Gherardini L, Meneghetti M, Herrero MA, Bianco A, et al. In vivo degradation of functionalized carbon nanotubes after stereotactic administration in the brain cortex. Nanomedicine 2012;7:1485-94.