Skip to main content

Advertisement

Log in

Nanoparticle-Based Delivery to Treat Spinal Cord Injury—a Mini-review

  • Mini-Review
  • Theme: NIPTE Research and Perspective: Advances in Nanotechnology-Based Drug Delivery
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

There is an increasing need to develop improved and non-invasive strategies to treat spinal cord injury (SCI). Nanoparticles (NPs) are an enabling technology to improve drug delivery, modulate inflammatory responses, and restore functional responses following SCI. However, the complex pathophysiology associated with SCI presents several distinct challenges that must be overcome for sufficient NP drug delivery to the spinal cord. The objective of this mini-review is to highlight the physiological challenges and cell types available for modulation and discuss several promising advancements using NPs to improve SCI treatment. We will focus our discussion on recent innovative approaches in NP drug delivery and how the implementation of multifactorial approaches to address the proinflammatory and complex immune dysfunction in SCI offers significant potential to improve outcomes in SCI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. National Spinal Cord Injury Statistical Center, Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham, 2018.

  2. Ahuja CS, Wilson JR, Nori S, Kotter MRN, Druschel C, Curt A, et al. Traumatic spinal cord injury. Nat Rev Dis Primers. 2017;33(1):1–21.

    Google Scholar 

  3. Dumont CM, Margul DJ, Shea LD. Tissue engineering approaches to modulate the inflammatory milieu following spinal cord injury. Cells Tissues Organs. 2016;202:52–66.

    Article  CAS  PubMed  Google Scholar 

  4. Fouad K, Krajacic A, Tetzlaff W. Spinal cord injury and plasticity: opportunities and challenges. Brain Res Bull. 2011;84:337–42.

  5. Saraiva C, Praca C, Ferreira R, Santos T, Ferreira L, Bernardino L. Nanoparticle-mediated brain drug delivery: overcoming blood-brain barrier to treat neurodegenerative diseases. J Control Release. 2016;235:34–47.

    Article  CAS  PubMed  Google Scholar 

  6. Kwon BK, Okon E, Hillyer J, Mann C, Baptiste D, Weaver LC, et al. A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J Neurotrauma. 2011;28:1545–88.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Song YH, Agrawal NK, Griffin JM, Schmidt CE. Recent advances in nanotherapeutic strategies for spinal cord injury repair. Adv Drug Deliv Rev. 2019;148:38–59.

    Article  CAS  PubMed  Google Scholar 

  8. Zuidema JM, Gilbert RJ, Osterhout DJ. Nanoparticle technologies in the spinal cord. Cells Tissues Organs. 2016;202:102–15.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang MH, Slaby EM, Stephanie G, Yu C, Watts DM, Liu H, et al. Lipid-mediated insertion of toll-like receptor (TLR) ligands for facile immune cell engineering. Front Immunol. 2020;11:560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu H, Moynihan KD, Zheng Y, Szeto GL, Li AV, Huang B, et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature. 2014;507:519–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Biscans A, Coles A, Haraszti R, Echeverria D, Hassler M, Osborn M, et al. Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo. Nucleic Acids Res. 2019;47:1082–96.

    Article  CAS  PubMed  Google Scholar 

  12. Osborn MF, Coles AH, Biscans A, Haraszti RA, Roux L, Davis S, et al. Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways. Nucleic Acids Res. 2019;47:1070–81.

    Article  CAS  PubMed  Google Scholar 

  13. Casey LM, Kakade S, Decker JT, Rose JA, Deans K, Shea LD, et al. Cargo-less nanoparticles program innate immune cell responses to toll-like receptor activation. Biomaterials. 2019;218:119333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Correa S, Boehnke N, Barberio AE, Deiss-Yehiely E, Shi A, Oberlton B, et al. Tuning nanoparticle interactions with ovarian cancer through layer-by-layer modification of surface chemistry. ACS Nano. 2020;14:2224–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gammon JM, Jewell CM. Engineering immune tolerance with biomaterials. Adv Healthc Mater. 2019;8(4):e1801419.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Gomes AC, Mohsen M, Bachmann MF. Harnessing nanoparticles for immunomodulation and vaccines. Vaccines (Basel). 2017;5(1):6.

    Article  PubMed Central  CAS  Google Scholar 

  17. Evans BC, Fletcher RB, Kilchrist KV, Dailing EA, Mukalel AJ, Colazo JM, et al. An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles. Nat Commun. 2019;10:5012.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ziemba AM, Gilbert RJ. Biomaterials for local, controlled drug delivery to the injured spinal cord. Front Pharmacol. 2017;8:245.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Lasola JJM, Kamdem H, McDaniel MW, Pearson RM. Biomaterial-driven immunomodulation: cell biology-based strategies to mitigate severe inflammation and sepsis. Front Immunol. 2020;11:1726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fontana F, Figueiredo P, Bauleth-Ramos T, Correia A, Santos HA. Immunostimulation and immunosuppression: nanotechnology on the brink. Small Methods. 2018;2:1700347.

    Article  CAS  Google Scholar 

  21. Ifergan I, Miller SD. Potential for targeting myeloid cells in controlling CNS inflammation. Front Immunol. 2020;11:571897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99:28–51.

    Article  CAS  PubMed  Google Scholar 

  23. Calvo P, Gouritin B, Villarroya H, Eclancher F, Giannavola C, Klein C, et al. Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat. Eur J Neurosci. 2002;15:1317–26.

    Article  PubMed  Google Scholar 

  24. Figley SA, Khosravi R, Legasto JM, Tseng YF, Fehlings MG. Characterization of vascular disruption and blood-spinal cord barrier permeability following traumatic spinal cord injury. J Neurotrauma. 2014;31:541–52.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Park J, Zhang Y, Saito E, Gurczynski SJ, Moore BB, Cummings BJ, et al. Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury. Proc Natl Acad Sci U S A. 2019;116:14947–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jeong SJ, Cooper JG, Ifergan I, McGuire TL, Xu D, Hunter Z, et al. Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice. Neurobiol Dis. 2017;108:73–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brown JA, Faley SL, Shi Y, Hillgren KM, Sawada GA, Baker TK, et al. Advances in blood-brain barrier modeling in microphysiological systems highlight critical differences in opioid transport due to cortisol exposure. Fluids Barriers CNS. 2020;17:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Surnar B, Basu U, Banik B, Ahmad A, Marples B, Kolishetti N, et al. Nanotechnology-mediated crossing of two impermeable membranes to modulate the stars of the neurovascular unit for neuroprotection. Proc Natl Acad Sci. 2018;115:E12333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gonzalez-Carter D, Liu X, Tockary TA, Dirisala A, Toh K, Anraku Y, et al. Targeting nanoparticles to the brain by exploiting the blood-brain barrier impermeability to selectively label the brain endothelium. Proc Natl Acad Sci U S A. 2020;117:19141–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cerqueira SR, Ayad NG, Lee JK. Neuroinflammation treatment via targeted delivery of nanoparticles. Front Cell Neurosci. 2020;14:576037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yun X, Maximov VD, Yu J, Zhu H, Vertegel AA, Kindy MS. Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury. J Cereb Blood Flow Metab. 2013;33:583–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pearson RM, Juettner V, Hong S. Biomolecular corona on nanoparticles: a survey of recent literature and its implications in targeted drug delivery. Front Chem. 2014;2. https://doi.org/10.3389/fchem.2014.00108.

  33. Pearson RM, Hsu H-j, Bugno J, Hong S. Understanding nano-bio interactions to improve nanocarriers for drug delivery. MRS Bull. 2014;39:227–37.

    Article  CAS  Google Scholar 

  34. Siebert JR, Conta Steencken A, Osterhout DJ. Chondroitin sulfate proteoglycans in the nervous system: inhibitors to repair. Biomed Res Int. 2014;2014:845323.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Mann AP, Scodeller P, Hussain S, Joo J, Kwon E, Braun GB, et al. A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries. Nat Commun. 2016;7:11980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sun G, Zeng S, Liu X, Shi H, Zhang R, Wang B, et al. Synthesis and characterization of a silica-based drug delivery system for spinal cord injury therapy. Nano-Micro Lett. 2019;11:23.

    Article  CAS  Google Scholar 

  37. Jiang Z, Guan J, Qian J, Zhan C. Peptide ligand-mediated targeted drug delivery of nanomedicines. Biomater Sci. 2019;7:461–71.

    Article  CAS  PubMed  Google Scholar 

  38. Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 2008;209:378–88.

    Article  CAS  PubMed  Google Scholar 

  39. Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013;39:3–18.

    Article  CAS  PubMed  Google Scholar 

  40. Papa S, Ferrari R, De Paola M, Rossi F, Mariani A, Caron I, et al. Polymeric nanoparticle system to target activated microglia/macrophages in spinal cord injury. J Control Release. 2014;174:15–26.

    Article  CAS  PubMed  Google Scholar 

  41. Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004;5:146–56.

    Article  CAS  PubMed  Google Scholar 

  42. Chung W-S, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504:394–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nguyen KB, Pender MP. Phagocytosis of apoptotic lymphocytes by oligodendrocytes in experimental autoimmune encephalomyelitis. Acta Neuropathol. 1997;95:40–6.

    Article  Google Scholar 

  44. Scheib JL, Höke A. An attenuated immune response by Schwann cells and macrophages inhibits nerve regeneration in aged rats. Neurobiol Aging. 2016;45:1–9.

    Article  CAS  PubMed  Google Scholar 

  45. Mosher KI, Andres RH, Fukuhara T, Bieri G, Hasegawa-Moriyama M, He Y, et al. Neural progenitor cells regulate microglia functions and activity. Nat Neurosci. 2012;15:1485–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wu H-H, Bellmunt E, Scheib JL, Venegas V, Burkert C, Reichardt LF, et al. Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nat Neurosci. 2009;12:1534–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bradbury EJ, Burnside ER. Moving beyond the glial scar for spinal cord repair. Nat Commun. 2019;10:3879.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Trivedi A, Olivas AD, Noble-Haeusslein LJ. Inflammation and spinal cord injury: infiltrating leukocytes as determinants of injury and repair processes. Clin Neurosci Res. 2006;6:283–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kopp MA, Liebscher T, Watzlawick R, Martus P, Laufer S, Blex C, et al. SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol. BMJ Open. 2016;6:e010651.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Xu J, Fan G, Chen S, Wu Y, Xu XM, Hsu CY. Methylprednisolone inhibition of TNF-alpha expression and NF-kB activation after spinal cord injury in rats. Brain Res Mol Brain Res. 1998;59:135–42.

    Article  CAS  PubMed  Google Scholar 

  51. Mothe AJ, Tassew NG, Shabanzadeh AP, Penheiro R, Vigouroux RJ, Huang L, et al. RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. Sci Rep. 2017;7:10529.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Qian T, Guo X, Levi AD, Vanni S, Shebert RT, Sipski ML. High-dose methylprednisolone may cause myopathy in acute spinal cord injury patients. Spinal Cord. 2005;43:199–203.

    Article  CAS  PubMed  Google Scholar 

  53. Suberviola B, González-Castro A, Llorca J, Ortiz-Melón F, Miñambres E. Early complications of high-dose methylprednisolone in acute spinal cord injury patients. Injury. 2008;39:748–52.

    Article  PubMed  Google Scholar 

  54. Cerqueira SR, Oliveira JM, Silva NA, Leite-Almeida H, Ribeiro-Samy S, Almeida A, et al. Microglia response and in vivo therapeutic potential of methylprednisolone-loaded dendrimer nanoparticles in spinal cord injury. Small. 2013;9:738–49.

    Article  CAS  PubMed  Google Scholar 

  55. Kim YT, Caldwell JM, Bellamkonda RV. Nanoparticle-mediated local delivery of methylprednisolone after spinal cord injury. Biomaterials. 2009;30:2582–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Qi L, Jiang H, Cui X, Liang G, Gao M, Huang Z, et al. Synthesis of methylprednisolone loaded ibuprofen modified dextran based nanoparticles and their application for drug delivery in acute spinal cord injury. Oncotarget. 2017;8(59):99666–80.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Andrea Bighinati MLF, Gualandi C, Pannella M, Giuliani A, Beggiato S, Ferraro L, et al. Improved functional recovery in rat spinal cord injury induced by a drug combination administered with an implantable polymeric delivery system. J Neurotrauma. 2020;37:1708–19.

    Article  PubMed  Google Scholar 

  58. Saxena T, Loomis KH, Pai SB, Karumbaiah L, Gaupp E, Patil K, et al. Nanocarrier-mediated inhibition of macrophage migration inhibitory factor attenuates secondary injury after spinal cord injury. ACS Nano. 2015;9:1492–505.

    Article  CAS  PubMed  Google Scholar 

  59. Wu W, Lee S-Y, Wu X, Tyler JY, Wang H, Ouyang Z, et al. Neuroprotective ferulic acid (FA)–glycol chitosan (GC) nanoparticles for functional restoration of traumatically injured spinal cord. Biomaterials. 2014;35:2355–64.

    Article  CAS  PubMed  Google Scholar 

  60. Sun G, Yang S, Cai H, Shu Y, Han Q, Wang B, et al. Molybdenum disulfide nanoflowers mediated anti-inflammation macrophage modulation for spinal cord injury treatment. J Colloid Interface Sci. 2019;549:50–62.

    Article  CAS  PubMed  Google Scholar 

  61. Shi Y, Kim S, Huff TB, Borgens RB, Park K, Shi R, et al. Effective repair of traumatically injured spinal cord by nanoscale block copolymer micelles. Nat Nanotechnol. 2010;5:80–7.

    Article  CAS  PubMed  Google Scholar 

  62. Liu D, Chen J, Jiang T, Li W, Huang Y, Lu X, et al. Biodegradable spheres protect traumatically injured spinal cord by alleviating the glutamate-induced excitotoxicity. Adv Mater. 2018;30:1706032.

    Article  CAS  Google Scholar 

  63. Gao W, Li J. Targeted siRNA delivery reduces nitric oxide mediated cell death after spinal cord injury. J Nanobiotechnol. 2017;15:38.

    Article  CAS  Google Scholar 

  64. Liu Z, Jiang M, Kang T, Miao D, Gu G, Song Q, et al. Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration. Biomaterials. 2013;34:3870–81.

    Article  CAS  PubMed  Google Scholar 

  65. Ren H, Han M, Zhou J, Zheng Z-F, Lu P, Wang J-J, et al. Repair of spinal cord injury by inhibition of astrocyte growth and inflammatory factor synthesis through local delivery of flavopiridol in PLGA nanoparticles. Biomaterials. 2014;35:6585–94.

    Article  CAS  PubMed  Google Scholar 

  66. Wu J, Jiang H, Bi Q, Luo Q, Li J, Zhang Y, et al. Apamin-mediated actively targeted drug delivery for treatment of spinal cord injury: more than just a concept. Mol Pharm. 2014;11:3210–22.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by startup funds by the University of Maryland School of Pharmacy, the New Investigator Award from the American Association of Colleges of Pharmacy (AACP), and the University of Maryland Baltimore Institute for Clinical and Translational Research (ICTR) Accelerated Translational Incubator Pilot Grant (NIH #1UL1TR003098) awarded to R.M.P.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Courtney M. Dumont or Ryan M. Pearson.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Guest Editors: Xiuling Lu and Aliasger K Salem

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Atanu Chakraborty and Andrew J. Ciciriello are co-first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chakraborty, A., Ciciriello, A.J., Dumont, C.M. et al. Nanoparticle-Based Delivery to Treat Spinal Cord Injury—a Mini-review. AAPS PharmSciTech 22, 101 (2021). https://doi.org/10.1208/s12249-021-01975-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-021-01975-2

Key words

Navigation