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.

Autores de CIPF

• 

  Esther Giraldo Reboloso

  Autor

• Vicent Josep Nebot Carda

  Autor

• Snezana Dordevic

  Autor

• Ana Alastrue Agudo

  Autor

• Oleksandr Zagorodko

  Autor

• 

  Ana Armiñan De Benito

  Autor

• Beatriz Martinez Rojas

  Autor

• 

  Maria Jesus Vicent Docon

  Autor

• 

  M Victoria Moreno Manzano

  Autor

Participantes ajenos a CIPF

• Requejo-Aguilar R

Grupos de Investigación

• Laboratorio de Polímeros Terapéuticos

  

  Jefe/a de Grupo

  Maria Jesus Vicent Docon

• Laboratorio de Regeneración Tisular y Neuronal

  

  Jefe/a de Grupo

  M Victoria Moreno Manzano

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