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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.

التفاصيل البيبلوغرافية
العنوان: 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.
المؤلفون: Giraldo E; Neuronal and Tissue Regeneration Lab. Prince Felipe Research Institute, Valencia, Spain; Department of Biotechnology. Universitat Politècnica de València, Valencia, Spain., Nebot VJ; Polymer Therapeutics Lab. Prince Felipe Research Institute, Valencia, Spain; PTS S.L., Valencia, Spain., Đorđević S; Polymer Therapeutics Lab. Prince Felipe Research Institute, Valencia, Spain., Requejo-Aguilar R; 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., Alastrue-Agudo A; Neuronal and Tissue Regeneration Lab. Prince Felipe Research Institute, Valencia, Spain., Zagorodko O; Polymer Therapeutics Lab. Prince Felipe Research Institute, Valencia, Spain., Armiñan A; Polymer Therapeutics Lab. Prince Felipe Research Institute, Valencia, Spain., Martinez-Rojas B; Neuronal and Tissue Regeneration Lab. Prince Felipe Research Institute, Valencia, Spain., Vicent MJ; Polymer Therapeutics Lab. Prince Felipe Research Institute, Valencia, Spain. Electronic address: mjvicent@cipf.es., Moreno-Manzano V; Neuronal and Tissue Regeneration Lab. Prince Felipe Research Institute, Valencia, Spain. Electronic address: vmorenom@cipf.es.
المصدر: Biomaterials [Biomaterials] 2021 Sep; Vol. 276, pp. 121052. Date of Electronic Publication: 2021 Jul 29.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 8100316 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-5905 (Electronic) Linking ISSN: 01429612 NLM ISO Abbreviation: Biomaterials Subsets: MEDLINE
أسماء مطبوعة: Publication: <1995-> : Amsterdam : Elsevier Science
Original Publication: [Guilford, England] : IPC Science and Technology Press, 1980-
مواضيع طبية MeSH: Neural Stem Cells* , Spinal Cord Injuries*/drug therapy, Animals ; Polymers ; Rats ; rho-Associated Kinases
مستخلص: 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.
(Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
فهرسة مساهمة: Keywords: Axonal elongation; Fasudil; Neuroprotection; Polymer therapeutics; Polymer-drug conjugates; RhoA/ROCK Inhibitor; Spinal cord injury
المشرفين على المادة: 0 (Polymers)
EC 2.7.11.1 (rho-Associated Kinases)
تواريخ الأحداث: Date Created: 20210813 Date Completed: 20210920 Latest Revision: 20210920
رمز التحديث: 20221213
DOI: 10.1016/j.biomaterials.2021.121052
PMID: 34388362
قاعدة البيانات: MEDLINE
الوصف
تدمد:1878-5905
DOI:10.1016/j.biomaterials.2021.121052