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

• Published in: Biomaterials Vol. 276; p. 121052
• Main Authors: Giraldo, E., Nebot, V.J., Đorđević, S., Requejo-Aguilar, R., Alastrue-Agudo, A., Zagorodko, O., Armiñan, A., Martinez-Rojas, B., Vicent, M.J., Moreno-Manzano, V.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-09-2021
• Subjects: Axonal elongation; Fasudil; Neuroprotection; Polymer therapeutics; Polymer-drug conjugates; RhoA/ROCK Inhibitor; Spinal cord injury; RhoA/ROCK Inhibitor; Neuroprotection; Polymer-drug conjugates; Axonal elongation; Polymer therapeutics; Spinal cord injury; Fasudil
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2021.121052

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.
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•Polypeptide conjugation of the Rho kinase inhibitor fasudil (PGA-SS-F) allows sustained drug release.•PGA-SS-F supports improved neuroprotective and regenerative activity in an in vivo model of acute spinal cord injury.•PGA-SS-F treatment of transplanted neural progenitor cells in vivo improves tissue engraftment and cell survival.