2. Academic Validation
  3. A rationally designed self-immolative linker enhances the synergism between a polymer-rock inhibitor conjugate and neural progenitor cells in the treatment of spinal cord injury

A rationally designed self-immolative linker enhances the synergism between a polymer-rock inhibitor conjugate and neural progenitor cells in the treatment of spinal cord injury

  • Biomaterials. 2021 Sep;276:121052. doi: 10.1016/j.biomaterials.2021.121052.
E Giraldo 1,  V J Nebot 2,  S Đorđević 3,  R Requejo-Aguilar 4,  A Alastrue-Agudo 5,  O Zagorodko 3,  A Armiñan 3,  B Martinez-Rojas 5,  M J Vicent 6,  V Moreno-Manzano 7
Affiliations

Affiliations

  • 1 Neuronal and Tissue Regeneration Lab. Prince Felipe Research Institute, Valencia, Spain; Department of Biotechnology. Universitat Politècnica de València, Valencia, Spain.
  • 2 Polymer Therapeutics Lab. Prince Felipe Research Institute, Valencia, Spain; PTS S.L., Valencia, Spain.
  • 3 Polymer Therapeutics Lab. Prince Felipe Research Institute, Valencia, Spain.
  • 4 Neuronal and Tissue Regeneration Lab. Prince Felipe Research Institute, Valencia, Spain; Dept. Biochemistry and Molecular Biology, University of Cordoba, Cordoba, Spain. Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain.
  • 5 Neuronal and Tissue Regeneration Lab. Prince Felipe Research Institute, Valencia, Spain.
  • 6 Polymer Therapeutics Lab. Prince Felipe Research Institute, Valencia, Spain. Electronic address: mjvicent@cipf.es.
  • 7 Neuronal and Tissue Regeneration Lab. Prince Felipe Research Institute, Valencia, Spain. Electronic address: vmorenom@cipf.es.
PMID: 34388362 DOI: 10.1016/j.biomaterials.2021.121052
Abstract

Rho/ROCK signaling induced after spinal cord injury (SCI) contributes to secondary damage by promoting Apoptosis, inflammation, and axon growth inhibition. The specific Rho-kinase inhibitor fasudil can contribute to functional regeneration after SCI, although inherent low stability has hampered its use. To improve the therapeutic potential of fasudil, we now describe a family of rationally-designed bioresponsive polymer-fasudil conjugates based on an understanding of the conditions after SCI, such as low pH, enhanced expression of specific proteases, and a reductive environment. Fasudil conjugated to poly-l-glutamate via a self-immolative redox-sensitive linker (PGA-SS-F) displays optimal release kinetics and, consequently, treatment with PGA-SS-F significantly induces neurite elongation and axon growth in dorsal root ganglia explants, spinal cord organotypic cultures, and neural precursor cells (NPCs). The intrathecal administration of PGA-SS-F after SCI in a rat model prevents early Apoptosis and induces the expression of axonal growth- and neuroplasticity-associated markers to a higher extent than the free form of fasudil. Moreover, a combination treatment comprising the acute transplantation of NPCs pre-treated with PGA-SS-F leads to enhanced cell engraftment and reduced cyst formation after SCI. In chronic SCI, combinatory treatment increases the preservation of neuronal fibers. Overall, this synergistic combinatorial strategy may represent a potentially efficient clinical approach to SCI treatment.

Keywords

Axonal elongation; Fasudil; Neuroprotection; Polymer therapeutics; Polymer-drug conjugates; RhoA/ROCK Inhibitor; Spinal cord injury.

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