Giraldo, ENebot, V JĐorđević, SRequejo-Aguilar, RAlastrue-Agudo, AZagorodko, OArmiñan, AMartinez-Rojas, BVicent, M JMoreno-Manzano, V2023-02-092023-02-092021-07-24Giraldo E, Nebot VJ, Đorđević S, Requejo-Aguilar R, Alastrue-Agudo A, Zagorodko O, et al. 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;276:121052http://hdl.handle.net/10668/18369Rho/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.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Axonal elongationFasudilNeuroprotectionPolymer therapeuticsPolymer-drug conjugatesRhoA/ROCK InhibitorSpinal cord injuryAnimalsNeural stem cellsPolymersRatsSpinal cord injuriesrho-associated kinasesresearch article34388362open accessAnimalesCélulas-madre neuralesPolímerosQuinasas asociadas a rhoRatasTraumatismos de la médula espinal10.1016/j.biomaterials.2021.1210521878-5905https://doi.org/10.1016/j.biomaterials.2021.121052