RT Journal Article
T1 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.
A1 Giraldo, E
A1 Nebot, V J
A1 Đorđević, S
A1 Requejo-Aguilar, R
A1 Alastrue-Agudo, A
A1 Zagorodko, O
A1 Armiñan, A
A1 Martinez-Rojas, B
A1 Vicent, M J
A1 Moreno-Manzano, V
K1 Axonal elongation
K1 Fasudil
K1 Neuroprotection
K1 Polymer therapeutics
K1 Polymer-drug conjugates
K1 RhoA/ROCK Inhibitor
K1 Spinal cord injury
AB 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.
PB Elsevier
YR 2021
FD 2021-07-24
LK http://hdl.handle.net/10668/18369
UL http://hdl.handle.net/10668/18369
LA en
NO Giraldo 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;276:121052
NO This research was funded by FEDER/Ministerio de Ciencia e Innovación – Agencia Estatal de Investigación [RTI2018-095872-B-C21/ERDF], Ministerio de Ciencia e Innovación [SAF2016-80427-R,PID2019-108806RB-I00], Fundació  Marató TV3 [20172230, 20172231and 20172110] Fundación Step by Step, Agencia Valenciana deInnovación (AVI) [INNVAL10/19/047] and MINECO/FEDER, UE;Fondo Europeo de Desarrollo Regional (FEDER) incluido en el ProgramaOperativo FEDER de la Comunidad Valenciana 2014–2020.
DS RISalud
RD Apr 7, 2025